Check out the articles published by members of our group in the last 5 years.
- Finerenone protects against progression of kidney and cardiovascular damage in a model of type 1 diabetes through modulation of proinflammatory and osteogenic factors.
Sanz-Gómez M, Manzano-Lista FJ, Vega-Martín E, González-Moreno D, Alcalá M, Gil-Ortega M, Somoza B, Pizzamiglio C, Ruilope LM, Aránguez I, Kolkhof P, Kreutz R, Fernández-Alfonso MS.Biomed Pharmacother. 2023 Oct 11;168:115661. doi: 10.1016/j.biopha.2023.115661
- Short-term dietary intervention improves endothelial dysfunction induced by high-fat feeding in mice through upregulation of the AMPK-CREB signaling pathway.
González-Blázquez R, Gil-Ortega M, Alcalá M, González-Moreno D, Viana M, Chowen JA, Sanz-Gómez M, Fernández-Alfonso MS, Somoza B. Acta Physiol (Oxf). 2023 Aug 8:e14023. doi: 10.1111/apha.14023.
Aim: In addition to functioning as an energy sensor switch, AMPK plays a key role in the maintenance of cardiovascular homeostasis. However, obesity disrupts AMPK signaling, contributing to endothelial dysfunction and cardiovascular disease. This study aimed to elucidate if a short-term dietary intervention consisting in replacing the high-fat diet with a standard diet for 2 weeks could reverse obesity-induced endothelial dysfunction via AMPK-CREB activation.
Methods: For this, 5-week-old male C57BL6J mice were fed a standard (Chow) or a high-fat (HF) diet for 8 weeks. The HF diet was replaced by the chow diet for the last 2 weeks in half of HF mice, generating 3 groups: Chow, HF and HF-Chow. Vascular reactivity and western-blot assays were performed in the thoracic aorta.
Results: Returning to a chow diet significantly reduced body weight and glucose intolerance. Relaxant responses to acetylcholine and the AMPK activator (AICAR) were significantly impaired in HF mice but improved in HF-Chow mice. The protein levels of AMPKα, p-CREB and antioxidant systems (heme oxygenase-1 (HO-1) and catalase) were significantly reduced in HF but normalized in HF-Chow mice.
Conclusion: Improving dietary intake by replacing a HF diet with a standard diet improves AMPK-mediated responses due to the upregulation of the AMPK/CREB/HO-1 signaling pathway.
- Angiotensin II type 2 receptor as a novel activator of brown adipose tissue in obesity.
Alvarez-Gallego F, González-Blázquez R, Gil-Ortega M, Somoza B, Calderón-Dominguez M, Moratinos J, Garcia-Garcia V, Fernández P, González-Moreno D, Viana M, Alcalá M. Biofactors. 2023 Jun 7. doi: 10.1002/biof.1981. Epub ahead of print.
The angiotensin II type 2 receptor (AT2R) exerts vasorelaxant, anti-inflammatory, and antioxidant properties. In obesity, its activation counterbalances the adverse cardiovascular effects of angiotensin II mediated by the AT1R. Preliminary results indicate that it also promotes brown adipocyte differentiation in vitro. Our hypothesis is that AT2R activation could increase BAT mass and activity in obesity. Five-week-old male C57BL/6J mice were fed a standard or a high-fat (HF) diet for 6 weeks. Half of the animals were treated with compound 21 (C21), a selective AT2R agonist, (1 mg/kg/day) in the drinking water. Electron transport chain (ETC), oxidative phosphorylation, and UCP1 proteins were measured in the interscapular BAT (iBAT) and thoracic perivascular adipose tissue (tPVAT) as well as inflammatory and oxidative parameters. Differentiation and oxygen consumption rate (OCR) in the presence of C21 was tested in brown preadipocytes. In vitro, C21-differentiated brown adipocytes showed an AT2R-dependent increase of differentiation markers (Ucp1, Cidea, Pparg) and increased basal and H+ leak-linked OCR. In vivo, HF-C21 mice showed increased iBAT mass compared to HF animals. Both their iBAT and tPVAT showed higher protein levels of the ETC protein complexes and UCP1, together with a reduction of inflammatory and oxidative markers. The activation of the AT2R increases BAT mass, mitochondrial activity, and reduces markers of tissue inflammation and oxidative stress in obesity. Therefore, insulin reduction and better vascular responses are achieved. Thus, the activation of the protective arm of the renin-angiotensin system arises as a promising tool in the treatment of obesity.
- Generation of Highly Antioxidant Submicron Particles from Myrtus communis Leaf Extract by Supercritical Antisolvent Extraction Process.
Valor D, Montes A, Calderón-Domínguez M, Aghziel I, Sánchez-Gomar I, Alcalá M, Durán-Ruiz MC, Pereyra C. Antioxidants (Basel). 2023 Feb 20;12(2):530.
Submicron particles have been produced from an ethanolic extract of Myrtus communnis leaves using supercritical carbon dioxide technology, hereinafter referred to as Supercritical Antisolvent Extraction (SAE). The influence of pressure (9-20 MPa), temperature (308 and 328 K) and injection rate (3 and 8 mL/min) on the particles’ precipitation has been investigated, and it has been confirmed that increases in pressure and temperature led to smaller particle sizes. The obtained particles had a quasi-spherical shape with sizes ranging from 0.42 to 1.32 μm. Moreover, the bioactivity of the generated particles was assessed and large contents of phenolic compounds with a high antioxidant activity were measured. The particles were also subjected to in vitro studies against oxidative stress. The myrtle particles demonstrated cytoprotective properties when applied at low concentrations (1 μM) to macrophage cell lines.
- Sex-Specific Relationships of Physical Activity and Sedentary Behaviour with Oxidative Stress and Inflammatory Markers in Young Adults.
Corral-Pérez J, Alcala M, Velázquez-Díaz D, Perez-Bey A, Vázquez-Sánchez MÁ, Calderon-Dominguez M, Casals C, Ponce-González JG. Int J Environ Res Public Health. 2023 Jan 4;20(2):899.
This study aims to analyse sex-specific associations of physical activity and sedentary behaviour with oxidative stress and inflammatory markers in a young-adult population. Sixty participants (21 women, 22.63 ± 4.62 years old) wore a hip accelerometer for 7 consecutive days to estimate their physical activity and sedentarism. Oxidative stress (catalase, superoxide dismutase, glutathione peroxidase, glutathione, malondialdehyde, and advanced oxidation protein products) and inflammatory (tumour necrosis factor-alpha and interleukin-6) markers were measured. Student t-tests and single linear regressions were applied. The women presented higher catalase activity and glutathione concentrations, and lower levels of advanced protein-oxidation products, tumour necrosis factor-alpha, and interleukin-6 than the men (p < 0.05). In the men, longer sedentary time was associated with lower catalase activity (β = -0.315, p = 0.04), and longer sedentary breaks and higher physical-activity expenditures were associated with malondialdehyde (β = -0.308, p = 0.04). Vigorous physical activity was related to inflammatory markers in the women (tumour necrosis factor-alpha, β = 0.437, p = 0.02) and men (interleukin-6, β = 0.528, p < 0.01). In conclusion, the women presented a better redox and inflammatory status than the men; however, oxidative-stress markers were associated with physical activity and sedentary behaviours only in the men. In light of this, women could have better protection against the deleterious effect of sedentarism but a worse adaptation to daily physical activity.
- Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury.
Sastourné-Arrey Q, Mathieu M, Contreras X, Monferran S, Bourlier V, Gil-Ortega M, Murphy E, Laurens C, Varin A, Guissard C, Barreau C, André M, Juin N, Marquès M, Chaput B, Moro C, O’Gorman D, Casteilla L, Girousse A, Sengenès C. Nat Commun. 2023 Jan 5;14(1):80
Fibro-adipogenic progenitors (FAPs) play a crucial role in skeletal muscle regeneration, as they generate a favorable niche that allows satellite cells to perform efficient muscle regeneration. After muscle injury, FAP content increases rapidly within the injured muscle, the origin of which has been attributed to their proliferation within the muscle itself. However, recent single-cell RNAseq approaches have revealed phenotype and functional heterogeneity in FAPs, raising the question of how this differentiation of regenerative subtypes occurs. Here we report that FAP-like cells residing in subcutaneous adipose tissue (ScAT), the adipose stromal cells (ASCs), are rapidly released from ScAT in response to muscle injury. Additionally, we find that released ASCs infiltrate the damaged muscle, via a platelet-dependent mechanism and thus contribute to the FAP heterogeneity. Moreover, we show that either blocking ASCs infiltration or removing ASCs tissue source impair muscle regeneration. Collectively, our data reveal that ScAT is an unsuspected physiological reservoir of regenerative cells that support skeletal muscle regeneration, underlining a beneficial relationship between muscle and fat.
- Imbalance in Bone Morphogenic Proteins 2 and 7 Is Associated with Renal and Cardiovascular Damage in Chronic Kidney Disease.
Manzano-Lista FJ, Sanz-Gómez M, González-Moreno D, Vega-Martín E, Gil-Ortega M, Schulz A, Rubio MÁ, Ruiz-Hurtado G, Ruilope LM, Aránguez I, Kreutz R, Fernández-Alfonso MS. Int J Mol Sci. 2022 Dec 20;24(1):40.
Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 were determined by ELISA in CKD patients (stages I-III; n = 95) and Munich Wistar Frömter (MWF) rats. Age-matched Wistar rats were used as a control. The expression of BMP-2, BMP-7, and profibrotic and calcification factors was determined in kidney and perivascular adipose tissues (PVAT). BMP-2 was higher in stage III CKD patients compared to control subjects. BMP-7 was lower at any CKD stage compared to controls, with a significant further reduction in stage III patients. A similar imbalance was observed in MWF rats together with the increase in systolic (SBP) and diastolic blood pressure (DBP), or pulse wave velocity (PWV). MWF exhibited elevated urinary albumin excretion (UAE) and renal expression of BMP-2 or kidney damage markers, Kim-1 and Ngal, whereas renal BMP-7 was significantly lower than in Wistar rats. SBP, DBP, PWV, UAE, and plasma creatinine positively correlated with the plasma BMP-2/BMP-7 ratio. Periaortic and mesenteric PVAT from MWF rats showed an increased expression of BMP-2 and profibrotic and calcification markers compared to Wistar rats, together with a reduced BMP-7 expression. BMP-2 and BMP-7 imbalance in plasma, kidney, and PVATs is associated with vascular damage, suggesting a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, their combined analysis stratified by CKD stages might be of clinical interest to provide information about the degree of renal and vascular damage in CKD.
- Role of long non-coding RNAs in adipose tissue metabolism and associated pathologies.
Corral A, Alcala M, Carmen Duran-Ruiz M, I Arroba A, Ponce-Gonzalez JG, Todorčević M, Serra D, Calderon-Dominguez M, Herrero L. Biochem Pharmacol. 2022 Oct 19:115305.
The incidence of obesity and its related disorders has increased dramatically in recent years and has become a pandemic. Adipose tissue is a crucial regulator of these diseases due to its endocrine capacity. Thus, understanding adipose tissue metabolism is essential to finding new effective therapeutic approaches. The “omic” revolution has identified new concepts about the complexity of the signaling pathways involved in the pathophysiology of adipose tissue-associated disorders. Specifically, advances in transcriptomics have allowed its application in clinical practice and primary or secondary prevention. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipose tissue since they can modulate gene expression at the epigenetic, transcriptional, and post-transcriptional levels. They interact with DNA, RNA, protein complexes, other non-coding RNAs, and microRNAs to regulate a wide range of physiological and pathological processes. Here, we review the emerging field of lncRNAs, including how they regulate adipose tissue biology, and discuss circulating lncRNAs, which may represent a turning point in the diagnosis and treatment of adipose tissue-associated disorders. We also highlight potential biomarkers of obesity and diabetes that could be considered as therapeutic targets
- Unravelling the Inflammatory Processes in the Early Stages of Diabetic Nephropathy and the Potential Effect of (Ss)-DS-ONJ.
Gómez-Jaramillo L, Cano-Cano F, Sánchez-Fernández EM, Ortiz Mellet C, García-Fernández JM, Alcalá M, Álvarez-Gallego F, Iturregui M, González-Montelongo MDC, Campos-Caro A, Arroba AI, Aguilar-Diosdado M. Int J Mol Sci. 2022 Jul 30;23(15):8450.
Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. The authors demonstrate that the glycolipid mimetic (Ss)-DS-ONJ is able to abolish inflammation via the induction of autophagy flux and provokes the inhibition of inflammasome complex in ex vivo and in vitro models, using adult kidney explants from BB rats. The contribution of (Ss)-DS-ONJ to reducing inflammatory events is mediated by the inhibition of classical stress kinase pathways and the blocking of inflammasome complex activation. The (Ss)-DS-ONJ treatment is able to inhibit the epithelial-to-mesenchymal transition (EMT) progression, but only when the IL18 levels are reduced by the treatment. These findings suggest that (Ss)-DS-ONJ could be a novel, and multifactorial treatment for DN.
- Adult kidney explants is a physiologic model for studying diabetic nephropathy.
Gómez-Jaramillo L, Cano-Cano F, Campos-Caro A, Álcala M, Álvarez-Gallego F, Arroba AI, Aguilar-Diosdado M. Life Sci. 2022 Jul 1;300:120575.
Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. In vitro approach using cell lines help to understand the mechanisms involves and allow the molecular and biochemical processes. Adult kidney (AK) explants remain an essential instrument for advancing our understanding of the molecular and cellular regulation of signalling pathways from an organotipic view with physiological system interaction integrated. AK explants from T1DM animal model (BB rat) are obtained by slicing central kidney area preserving the organ’s cytoarchitecture and reproduce the classical events detected during the DN in an in vivo model such as inflammation, epithelial-mesenchymal transition (EMT) processes by the modulation of a-SMA and e-Cadherin among others which have been determined by qRT-PCR, western-blot and immunohistochemistry. In this regard, AK explants reproduce the signalling pathways involve in DN progression (proinflammatory NFkB and inflammasome complex). This work demonstrates AK explants is a physiological experimental approach for studying the development and progression of DN. Furthermore, the inflammatory processes in AK explants under a diabetic environment and/or BB rats could be modulated by potential treatments for DN.
- Effects of saturated versus unsaturated fatty acids on metabolism, gliosis, and hypothalamic leptin sensitivity in male mice.
Fernández-Felipe J, Valencia-Avezuela M, Merino B, Somoza B, Cano V, Sanz-Martos AB, Frago LM, Fernández-Alfonso MS, Ruiz-Gayo M, Chowen JA. Nutr Neurosci. 2022 Feb 6:1-14.
Background: Development of obesity and its comorbidities is not only the result of excess energy intake, but also of dietary composition. Understanding how hypothalamic metabolic circuits interpret nutritional signals is fundamental to advance towards effective dietary interventions.
Objective: We aimed to determine the metabolic response to diets enriched in specific fatty acids.
Methods: Male mice received a diet enriched in unsaturated fatty acids (UOLF) or saturated fatty acids (SOLF) for 8 weeks.
Results: UOLF and SOLF mice gained more weight and adiposity, but with no difference between these two groups. Circulating leptin levels increased on both fatty acid-enriched diet, but were higher in UOLF mice, as were leptin mRNA levels in visceral adipose tissue. In contrast, serum non-esterified fatty acid levels only rose in SOLF mice. Hypothalamic mRNA levels of NPY decreased and of POMC increased in both UOLF and SOLF mice, but only SOLF mice showed signs of hypothalamic astrogliosis and affectation of central fatty acid metabolism. Exogenous leptin activated STAT3 in the hypothalamus of all groups, but the activation of AKT and mTOR and the decrease in AMPK activation in observed in controls and UOLF mice was not found in SOLF mice.
Conclusions: Diets rich in fatty acids increase body weight and adiposity even if energy intake is not increased, while increased intake of saturated and unsaturated fatty acids differentially modify metabolic parameters that could underlie more long-term comorbidities. Thus, more understanding of how specific nutrients affect metabolism, weight gain, and obesity associated complications is necessary.
- miR-16-5p Suppression Protects Human Cardiomyocytes against Endoplasmic Reticulum and Oxidative Stress-Induced Injury.
Toro R, Pérez-Serra A, Mangas A, Campuzano O, Sarquella-Brugada G, Quezada-Feijoo M, Ramos M, Alcalá M, Carrera E, García-Padilla C, Franco D, Bonet F. Int J Mol Sci. 2022 Jan 18;23(3):1036.
- Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK-eNOS-NO pathway.
Sanz-Gómez M, Aledavood E, Beroiz-Salaverri M, Lagartera L, Vega-Martín E, Gil-Ortega M, Cumella J, Pérez C, Luque FJ, Estarellas C, Fernández-Alfonso MS, Castro A. Sci Rep. 2022 Mar 10;12(1):4225
- AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice fed a high-fat diet.
González-Blázquez R, Alcalá M, Cárdenas-Rebollo JM, Viana M, Steckelings UM, Boisvert WA, Unger T, Fernández-Alfonso MS, Somoza B, Gil-Ortega M. Clin Sci (Lond). 2021 Dec 22;135(24):2763-2780
- Prevention of Teratogenesis in Pregnancies of Obese Rats by Vitamin E Supplementation.
Alcala M, Bolado VE, Sánchez-Vera I, Clapés S, Dasí F, Sáez G, Carrera E, Alvarez-Gallego F, Loeken MR, Viana M. Antioxidants (Basel). 2021 Jul 23;10(8):1173
Congenital malformations are a common adverse outcome in pregnancies complicated by pregestational obesity, although the underlying mechanisms are still unrevealed. Our aim was to study the effect of oxidative stress in obesity-induced teratogenesis. Wistar rats were fed a high-fat diet for 13 weeks, with (OE group) or without (O group) vitamin E supplementation. Then, rats were mated and sacrificed at day 11.5 of gestation. Embryos from O dams presented a 25.9 ± 3.5% rate of malformations (vs. 8.7 ± 3.4% in C rats), which was reduced in the OE group (11.5 ± 2.3%). Pregestational obesity induced hepatic protein and DNA oxidation and a decline in antioxidant enzymes. Importantly, glutathione content was also decreased, limiting the availability of this antioxidant in the embryos. Vitamin E supplementation efficiently maintained glutathione levels in the obese mothers, which could be used in their embryos to prevent oxidation-induced malformations. To test the effect of decreasing glutathione levels alone in a cell culture model of neuroepithelium, murine embryonic stem cells (ESC) were induced to form neuronal precursors and glutathione synthesis was inhibited with the gamma-glutamylcysteine synthesis inhibitor, buthionine sulfoximine (BSO). BSO inhibited the expression of Pax3, a gene required for neural tube closure that is also inhibited by oxidative stress. Taken together, our data indicate that obesity causes malformations through the depletion of maternal glutathione, thereby decreasing glutathione-dependent free radical scavenging in embryos, which can be prevented by vitamin E supplementation.
- C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors.
González-Blázquez R, Alcalá M, Fernández-Alfonso MS, Steckelings UM, Lorenzo MP, Viana M, Boisvert WA, Unger T, Gil-Ortega M, Somoza B. Clin Sci (Lond). 2021 May 14;135(9):1145-1163
- The real impact of COVID-19 on community pharmacy professionals as part of the primary health care frontier workforce in Spain.
Manouchehri M, Bhamra SK, Fernández-Alfonso M, Gil-Ortega M. J Pharm Pharmacogn Res. 2021. 9(6), 878-891
Context: Spain was at the epicenter of the pandemic. Health centers across Spanish territory were not able to respond to non-emergency enquiries, leaving community pharmacies as the first point of patient’s contact.
Aims: To investigate the impact of COVID-19 on the mental and physical health of community pharmacy teams across Spain.
Methods: A cross-sectional observational study was performed with community pharmacy professionals throughout Spain. A questionnaire designed by our collaborator from the United Kingdom was adapted to the Spanish population and launched between October 2020 and February 2021.
Results: A total of 98 participants responded to the questionnaire. The survey showed an 80% increase in workload. The pandemic had negatively impacted the well-being of community pharmacy professionals. The survey indicated a national shortage of medicines and personal protective equipment across Spain, particularly during the first peak. To adapt to this pandora’s box of COVID-19, 96% of the pharmacies changed their settings to improve patients and staff’s safety. Most of these changes were self-financed by the pharmacy owner. The pharmacists kept up to date with information released from the pharmacists’ college, General Pharmaceutical Council and the Spanish Society of Community Pharmacists. The Public domain purchased more (79%) immune booster supplements.
Conclusions: Community pharmacy professionals have faced tremendous mental, physical and professional pressure in providing adequate personal protective equipment and medication supply to their communities. They have provided more pharmaceutical services during the crisis, although they have not been recognized as essential workers by the healthcare system.
- Differential Deleterious Impact of Highly Saturated Versus Monounsaturated Fat Intake on Vascular Function, Structure, and Mechanics in Mice.
Vega-Martín E, Gil-Ortega M, González-Blázquez R, Benedito S, Fernández-Felipe J, Ruiz-Gayo M, Del Olmo N, Chowen JA, Frago LM, Somoza B, Fernández-Alfonso MS. Nutrients. 2021 Mar 19;13(3):1003.
Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA.
- Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy.
Rodríguez CM, Velásquez-Berrío M, Rúa C, Viana M, Abrahams VM, Cadavid AP, Alvarez AM. Front Physiol. 2021 Nov 29;12:706743.
- High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus.
Gutiérrez-Vega S, Armella A, Mennickent D, Loyola M, Covarrubias A, Ortega-Contreras B, Escudero C, Gonzalez M, Alcalá M, Ramos MDP, Viana M, Castro E, Leiva A, Guzmán-Gutiérrez E. PLoS One. 2020 Nov 24;15(11):e0242743
- Expression of Chitotriosidase in Macrophages Modulates Atherosclerotic Plaque Formation in Hyperlipidemic Mice.
Yap J, McCurdy S, Alcala M, Irei J, Garo J, Regan W, Lee BH, Kitamoto S, Boisvert WA. Front Physiol. 2020 Jun 23;11:714
Objective: To determine whether overexpression of the chitin degrading enzyme, chitotriosidase (CHIT1), modulates macrophage function and ameliorates atherosclerosis.
Approach and results: Using a mouse model that conditionally overexpresses CHIT1 in macrophages (CHIT1-Tg) crossbred with the Ldlr -/- mouse provided us with a means to investigate the effects of CHIT1 overexpression in the context of atherosclerosis. In vitro, CHIT1 overexpression by murine macrophages enhanced protein expression of IL-4, IL-8, and G-CSF by BMDM upon stimulation with a combination of lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Phosphorylation of ERK1/2 and Akt was also down regulated when exposed to the same inflammatory stimuli. Hyperlipidemic, Ldlr -/--CHIT1-Tg (CHIT1-OE) mice were fed a high-fat diet for 12 weeks in order to study CHIT1 overexpression in atherosclerosis. Although plaque size and lesion area were not affected by CHIT1 overexpression in vivo, the content of hyaluronic acid (HA) and collagen within atherosclerotic plaques of CHIT1-OE mice was significantly greater. Localization of both ECM components was markedly different between groups.
Conclusions: These data demonstrate that CHIT1 alters cytokine expression and signaling pathways of classically activated macrophages. In vivo, CHIT1 modifies ECM distribution and content in atherosclerotic plaques, both of which are important therapeutic targets.
- Relevance of control diet choice in metabolic studies: impact in glucose homeostasis and vascular function.
González-Blázquez R, Alcalá M, Fernández-Alfonso MS, Villa-Valverde P, Viana M, Gil-Ortega M, Somoza B. Sci Rep. 2020 Feb 19;10(1):2902
- Impact of caloric restriction on AMPK and endoplasmic reticulum stress in peripheral tissues and circulating peripheral blood mononuclear cells from Zucker rats.
Vega-Martín E, González-Blázquez R, Manzano-Lista FJ, Martín-Ramos M, García-Prieto CF, Viana M, Rubio MA, Calle-Pascual AL, Lionetti L, Somoza B, Fernández-Alfonso MS, Alcalá M, Gil-Ortega M. J Nutr Biochem. 2020 Apr;78:108342.
- Sex Differences in Placental Protein Expression and Efficiency in a Rat Model of Fetal Programming Induced by Maternal Undernutrition.
Phuthong S, Reyes-Hernández CG, Rodríguez-Rodríguez P, Ramiro-Cortijo D, Gil-Ortega M, González-Blázquez R, González MC, López de Pablo AL, Arribas SM. Int J Mol Sci. 2020 Dec 28;22(1):237.
- Fetal Undernutrition Induces Resistance Artery Remodeling and Stiffness in Male and Female Rats Independent of Hypertension.
Gutiérrez-Arzapalo PY, Rodríguez-Rodríguez P, Ramiro-Cortijo D, Gil-Ortega M, Somoza B, de Pablo ÁLL, González MDC, Arribas SM. Biomedicines. 2020 Oct 16;8(10):424.
- Finerenone Reduces Intrinsic Arterial Stiffness in Munich Wistar Frömter Rats, a Genetic Model of Chronic Kidney Disease.
Gil-Ortega M, Vega-Martín E, Martín-Ramos M, González-Blázquez R, Pulido-Olmo H, Ruiz-Hurtado G, Schulz A, Ruilope LM, Kolkhof P, Somoza B, Kreutz R, Fernández-Alfonso MS. Am J Nephrol. 2020;51(4):294-303
Background: Development of albuminuria and arterial stiffness in Munich Wistar Frömter (MWF) rats, a model of chronic kidney disease, is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction. Finerenone (FIN), a novel, nonsteroidal, potent, and selective mineralocorticoid receptor antagonist, improves endothelial dysfunction through enhancing nitric oxide (NO) bioavailability and decreasing superoxide anion levels due to an upregulation in vascular and renal superoxide dismutase activity. We hypothesize that FIN reduces arterial stiffness in this model associated to the reduction in albuminuria and matrix metalloproteinase (MMP)-2/9 activity.
Methods: Twelve-week-old MWF rats with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated with FIN (10 mg/kg/day, once-daily oral gavage) or with vehicle (control, C) for 4 weeks.
Results: Arterial stiffness was significantly higher in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN treatment significantly lowered β-index, a measure of intrinsic stiffness independent of geometry, in MWF (βMWF-FIN = 7.7 ± 0.4 vs. βMWF-C = 9.2 ± 0.5, p < 0.05) positively correlating with urinary albumin excretion. Elastin fenestrae area in the internal elastic lamina of MA from MWF-FIN was significantly larger (+377%, p < 0.05). FIN increased plasma pro-MMP-2 and decreased plasma MMP-2 and MMP-9 activities, correlating with reductions in β-index. MA from MWF-FIN exhibited higher NO bioavailability and reduced superoxide anion levels compared to MWF-C.
Conclusion: FIN treatment reduces intrinsic arterial stiffness in MA from MWF rats associated with changes in elastin organization, normalization of MMP-2 and MMP-9 activities, and reduction of oxidative stress. Moreover, reduction of arterial stiffness correlates with reduction in albuminuria.
- Estudio del comsumo de antibióticos en pacientes de farmacia comunitaria.
Gómez Martínez-Sagrera, P., Cárdenas, J. M., Martín, A., Gil Ortega, M., & Somoza, B. (2020). Pharmaceutical Care España, 22(1), 3–24.
Introducción: España presenta una de las cifras más elevadas de resistencias bacterianas de Europa y paralelamente se sitúa entre los países que más antibióticos consume. La participación del farmacéutico comunitario educando al paciente sobre el buen uso de los antibióticos es importante para conseguir los objetivos marcados en el PRAN 2019-21.
Objetivos: El objetivo de este estudio fue describir en pacientes de Farmacia Comunitaria: i) el tipo de antibiótico que el paciente retiraba, ii) el perfil de prescripción en Atención Primaria y iii) el conocimiento que los pacientes tenían sobre el tratamiento.
Métodos: Se realizó un estudio observacional descriptivo en 86 pacientes de 5 oficinas de farmacia. Para ello, se elaboró un cuestionario basado en el de Molinero y cols. (2018), al que se han incluido nuevas preguntas para evaluar el conocimiento y el tipo de infección/antibiótico que tenía el paciente
Resultados: El 90% de los pacientes encuestados mostró un buen conocimiento del tratamiento prescrito (duración y/o pauta); sin embargo, sólo un 56% retiraba el antibiótico sobrante en el punto SIGRE. El tratamiento antibiótico más utilizado en las infecciones más prevalentes en nuestro estudio, infecciones respiratorias y urinarias, siguió las recomendaciones de las guías terapéuticas, amoxicilina en el 39% y fosfomicina (75% mujeres)/ciprofloxacino (80% hombres), respectivamente.
Conclusiones: Las campañas dirigidas contra la resistencia a antibióticos están empezando a dar resultados positivos tanto en los pacientes como en los prescriptores de Atención Primaria. El farmacéutico comunitario constituye un pilar fundamental en la promoción del correcto uso de antibióticos.
- Caloric restriction induces H2O2 formation as a trigger of AMPK-eNOS-NO pathway in obese rats: Role for CAMKII.
García-Prieto CF, Gil-Ortega M, Plaza A, Manzano-Lista FJ, González-Blázquez R, Alcalá M, Rodríguez-Rodríguez P, Viana M, Aránguez I, Gollasch M, Somoza B, Fernández-Alfonso MS. Free Radic Biol Med. 2019 Aug 1;139:35-45
- Mechanisms of Impaired Brown Adipose Tissue Recruitment in Obesity.
Alcalá M, Calderon-Dominguez M, Serra D, Herrero L, Viana M. Front Physiol. 2019 Feb 13;10:94.
- Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice.
Sevillano J, Sánchez-Alonso MG, Zapatería B, Calderón M, Alcalá M, Limones M, Pita J, Gramage E, Vicente-Rodríguez M, Horrillo D, Medina-Gómez G, Obregón MJ, Viana M, Valladolid-Acebes I, Herradón G, Ramos-Álvarez MP. Diabetologia. 2019 Jan;62(1):123-135.
Methods: To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted Ptn-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3 months) to older age (15 months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24°C and 30°C. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1 μg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR).
Results: Ptn deletion was associated with a reduction in total body fat (20.2% in Ptn+/+ vs 13.9% in Ptn-/- mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn+/+ vs 273% in Ptn-/- mice). We found that Ptn-/- mice exhibited a significantly lower QUICKI value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn+/+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn-/- than Ptn+/+ mice (42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T3 and mitochondrial uncoupling protein-1 in the brown adipose tissue of Ptn-/- mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression of the brown adipocyte markers Cidea (20% reduction), Prdm16 (21% reduction), and Pgc1-α (also known as Ppargc1a, 11% reduction).
Conclusions/interpretation: Our results reveal for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynamics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatment of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.
- Beneficial effects of murtilla extract and madecassic acid on insulin sensitivity and endothelial function in a model of diet-induced obesity.
Arancibia-Radich J, González-Blázquez R, Alcalá M, Martín-Ramos M, Viana M, Arribas S, Delporte C, Fernández-Alfonso MS, Somoza B, Gil-Ortega M. Sci Rep. 2019 Jan 24;9(1):599.
- Effect of Bariatric Surgery on Abnormal MMP-9 and AMPK Activities: Potential Markers of Obesity-Related CV Risk.
García-Prieto CF, Gil-Ortega M, Vega-Martín E, Ramiro-Cortijo D, Martín-Ramos M, Bordiú E, Sanchez-Pernaute A, Torres A, Aránguez I, Fernández-Alfonso M, Rubio MA, Somoza B. Beneficial Front Physiol. 2019 May 8;10:553.
- The Release of Adipose Stromal Cells from Subcutaneous Adipose Tissue Regulates Ectopic Intramuscular Adipocyte Deposition.
Girousse A, Gil-Ortega M, Bourlier V, Bergeaud C, Sastourné-Arrey Q, Moro C, Barreau C, Guissard C, Vion J, Arnaud E, Pradère JP, Juin N, Casteilla L, Sengenès C. Cell Rep. 2019 Apr 9;27(2):323-333.e5
- Inflammatory stress and altered angiogenesis evoked by very high-fat diets in mouse liver.
Plaza A, Naranjo V, Blonda AM, Cano V, González-Martín C, Gil-Ortega M, Ruiz-Gayo M, Merino B. Endocrinol Diabetes Nutr (Engl Ed). 2019 Aug-Sep;66(7):434-442
Background: Non-alcoholic fatty liver disease (NAFLD), a condition that leads to fibrosis, is caused by intake of very high-fat diets (HFDs). However, while the negative impact on the liver of these diets has been an issue of interest, systematic research on the effect of HFDs are lacking.
Objective: To characterize the overall impact of HFDs on both molecular and morphological signs of liver remodeling.
Methods: A study was conducted on male C57BL/6J mice to assess the effect of 4- and 8-week HFDs (60% kcal from fat) on (i) liver steatosis and fibrosis, and (ii) expression of factors involved in inflammation and angiogenesis.
Results: After an 8-week HFD, vascular endothelial growth factor type-2 receptor (VEGF-R2) and fatty acid translocase/trombospondin-1 receptor (CD36) were overexpressed in liver tissue of mice given HFDs. These changes suggest impaired liver angiogenesis and occurred together with (i) increased GPR78-BiP and EIF2α phosphorylation, suggesting endoplasmic reticulum stress, (ii) induction of Col1a1 gene expression, a marker of fibrosis, and (iii) increased CD31 immunolabeling, consistent with active angiogenesis and fibrosis.
Conclusion: Our data show that very HFDs promote a rapid inflammatory response, as well as deregulation of angiogenesis, both consistent with development of liver fibrosis.
- Evaluación de la técnica inhalatoria y la adherencia al tratamiento con inhaladores en farmacia comunitaria.
González Robayna, M. M., Montejo Rubio, C., & Gil Ortega, M. (2019). Pharmaceutical Care España, 21(1), 41–64.
Introducción: La vía inhalatoria es de elección para la administración de la mayoría de los fármacos empleados en el tratamiento de las enfermedades pulmonares obstructivas. No obstante, una técnica inhalatoria incorrecta puede comprometer el control de dichas patologías.
Objetivos: El objetivo de este trabajo fue evaluar la técnica inhalatoria de los pacientes de una farmacia comunitaria y su adherencia al tratamiento.
Métodos: Se llevó a cabo un estudio observacional descriptivo transversal con 74 pacientes en tratamiento con inhaladores a los que se les encuestó sobre su técnica de inhalación y la adherencia al tratamiento. Además, se les solicitó una demostración práctica del manejo del inhalador.
Resultados: El 47% de los encuestados cometieron errores críticos de uso del inhalador, aunque el 97.3% creían saber utilizarlo correctamente. El error más frecuente fue no esperar al menos un minuto entre inhalaciones cuando era necesario repetir la dosis. Aunque el 96% de los encuestados refirió haber recibido información sobre cómo utilizar el inhalador, solo en un 1% fue impartida por farmacéuticos. El 47% de los pacientes presentó una buena adherencia al tratamiento, pero el 60% presentó algún tipo de incumplimiento, siendo el incumplimiento errático el más frecuente.
Este estudio demuestra que un elevado porcentaje de pacientes utiliza una técnica inhalatoria incorrecta y presenta una mala adherencia terapéutica, lo que puede contribuir a una menor efectividad del tratamiento y a un peor control de sus problemas de salud. Es necesario un papel más activo de los farmacéuticos comunitarios para evitar esta situación.
- Antioxidants and Oxidative Stress: Focus in Obese Pregnancies.
Alcala M, Gutierrez-Vega S, Castro E, Guzman-Gutiérrez E, Ramos-Álvarez MP, Viana M. Front Physiol. 2018 Nov 6;9:1569.
- Finerenone Attenuates Endothelial Dysfunction and Albuminuria in a Chronic Kidney Disease Model by a Reduction in Oxidative Stress.
González-Blázquez R, Somoza B, Gil-Ortega M, Martín Ramos M, Ramiro-Cortijo D, Vega-Martín E, Schulz A, Ruilope LM, Kolkhof P, Kreutz R, Fernández-Alfonso MS. Front Pharmacol. 2018 Oct 9;9:1131.
- Role of Perivascular Adipose Tissue in Health and Disease.
Fernández-Alfonso MS, Somoza B, Tsvetkov D, Kuczmanski A, Dashwood M, Gil-Ortega M. Compr Physiol. 2017 Dec 12;8(1):23-59
- Diabetes in pregnancy: a new decade of challenges ahead.
Schaefer-Graf U, Napoli A, Nolan CJ; Diabetic Pregnancy Study Group. Diabetologia. 2018 May;61(5):1012-1021
- Estudio observacional sobre el grado de conocimiento de los pacientes acerca del tratamiento con acenocumarol.
Gil Ortega, M., Gil Ortega, V., Somoza Hernández, B., & Cano González, V. (2018). Pharmaceutical Care España, 20(1), Pharm Care Esp. 2018; 20(1): 27–49
Introducción: El tratamiento con anticoagulantes orales derivados de cumarinas como el acenocumarol es bastante complejo pues, además de presentar un estrecho margen terapéutico, pueden interaccionar con numerosos fármacos, alimentos o productos de herbolario, favoreciendo la aparición de reacciones adversas y comprometiendo la seguridad del paciente anticoagulado.
Objetivos: El objetivo de este trabajo ha sido evaluar la relación entre el grado de conocimiento del paciente en tratamiento con acenocumarol y la aparición de efectos adversos derivados del mismo.
Métodos: Se realizó un estudio observacional descriptivo en 30 pacientes de 3 oficinas de farmacia y un centro de atención primaria de la Comunidad de Madrid. Para ello, se elaboró un cuestionario basado en el de Zeolla y cols. (2016), validado en EE.UU. para pacientes en tratamiento con warfarina y adaptado a nuestra zona geográfica y al tratamiento con acenocumarol.
Resultados: Del 67% de los pacientes encuestados que afirmaron haber solicitado y obtenido consejo sobre el tratamiento con acenocumarol, sólo el 56% adquirió un grado de conocimiento adecuado y únicamente el 29% demostró conocer los medicamentos y productos de herbolario/dietéticos que debe evitar el paciente anticoagulado. Además, se observó que dicho grado de conocimiento era significativamente mayor en los pacientes que no habían presentado efectos adversos asociados al tratamiento anticoagulante con anterioridad.Conclusiones: Un adecuado grado de conocimiento acerca del tratamiento con acenocumarol y las posibles interacciones del mismo con otros medicamentos que no requieren prescripción médica o productos de herbolario/dietéticos reduce significativamente el riesgo de presentar efectos adversos asociados al tratamiento anticoagulante
- Increased inflammation, oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice.
Alcalá M, Calderon-Dominguez M, Bustos E, Ramos P, Casals N, Serra D, Viana M, Herrero L. Sci Rep. 2017 Nov 22;7(1):16082.
- Short-term vitamin E treatment impairs reactive oxygen species signaling required for adipose tissue expansion, resulting in fatty liver and insulin resistance in obese mice.
Alcala M, Calderon-Dominguez M, Serra D, Herrero L, Ramos MP, Viana M. PLoS One. 2017 Oct 13;12(10):e0186579
Objectives: The use of antioxidant therapy in the treatment of oxidative stress-related diseases such as cardiovascular disease, diabetes or obesity remains controversial. Our aim is to demonstrate that antioxidant supplementation may promote negative effects if used before the establishment of oxidative stress due to a reduced ROS generation under physiological levels, in a mice model of obesity.
Methods: C57BL/6J mice were fed with a high-fat diet for 14 weeks, with (OE group) or without (O group) vitamin E supplementation.
Results: O mice developed a mild degree of obesity, which was not enough to induce metabolic alterations or oxidative stress. These animals exhibited a healthy expansion of retroperitoneal white adipose tissue (rpWAT) and the liver showed no signs of lipotoxicity. Interestingly, despite achieving a similar body weight, OE mice were insulin resistant. In the rpWAT they presented a reduced generation of ROS, even below physiological levels (C: 1651.0 ± 212.0; O: 3113 ± 284.7; OE: 917.6 ±104.4 RFU/mg protein. C vs OE p< 0.01). ROS decay may impair their action as second messengers, which could account for the reduced adipocyte differentiation, lipid transport and adipogenesis compared to the O group. Together, these processes limited the expansion of this fat pad and as a consequence, lipid flux shifted towards the liver, causing steatosis and hepatomegaly, which may contribute to the marked insulin resistance.
Conclusions: This study provides in vivo evidence for the role of ROS as second messengers in adipogenesis, lipid metabolism and insulin signaling. Reducing ROS generation below physiological levels when the oxidative process has not yet been established may be the cause of the controversial results obtained by antioxidant therapy.
- Vascular Dysfunction in Mother and Offspring During Preeclampsia: Contributions from Latin-American Countries.
Giachini FR, Galaviz-Hernandez C, Damiano AE, Viana M, Cadavid A, Asturizaga P, Teran E, Clapes S, Alcala M, Bueno J, Calderón-Domínguez M, Ramos MP, Lima VV, Sosa-Macias M, Martinez N, Roberts JM, Escudero C; RIVA-TREM. Curr Hypertens Rep. 2017 Oct 6;19(10):83
- Brown Adipose Tissue Bioenergetics: A New Methodological Approach.
Calderon-Dominguez M, Alcalá M, Sebastián D, Zorzano A, Viana M, Serra D, Herrero L. Adv Sci (Weinh). 2017 Mar 13;4(4):1600274
- CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis.
Baumer Y, McCurdy S, Alcala M, Mehta N, Lee BH, Ginsberg MH, Boisvert WA. Atherosclerosis. 2017 Jan;256:105-114.
Background and aims: Vascular smooth muscle cells (VSMC) migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. CD98 is a transmembrane protein made of two subunits, CD98 heavy chain (CD98hc) and one of six light chains, and is known to be involved in cell proliferation and survival. Because the influence of CD98hc on atherosclerosis development is unknown, our aim was to determine if CD98hc expressed on VSMC plays a role in shaping the morphology of atherosclerotic plaques by regulating VSMC function.
Methods: In addition to determining the role of CD98hc in VSMC proliferation and apoptosis, we utilized mice with SMC-specific deletion of CD98hc (CD98hcfl/flSM22αCre+) to determine the effects of CD98hc deficiency on VSMC function in atherosclerotic plaque.
Results: After culturing for 5 days in vitro, CD98hc-/- VSMC displayed dramatically reduced cell counts, reduced proliferation, as well as reduced migration compared to control VSMC. Analysis of aortic VSCM after 8 weeks of HFD showed a reduction in CD98hc-/- VSMC proliferation as well as increased apoptosis compared to controls. A long-term atherosclerosis study using SMC-CD98hc-/-/ldlr-/- mice was performed. Although total plaque area was unchanged, CD98hc-/- mice showed reduced presence of VSMC within the plaque (2.1 ± 0.4% vs. 4.3 ± 0.4% SM22α-positive area per plaque area, p < 0.05), decreased collagen content, as well as increased necrotic core area (25.8 ± 1.9% vs. 10.9 ± 1.6%, p < 0.05) compared to control ldlr-/- mice.
Conclusions: We conclude that CD98hc is required for VSMC proliferation, and that its deficiency leads to significantly reduced presence of VSMC in the neointima. Thus, CD98hc expression in VSMC contributes to the formation of plaques that are morphologically more stable, and thereby protects against atherothrombosis.
- Role of PVAT in coronary atherosclerosis and vein graft patency: friend or foe?
Fernández-Alfonso MS, Gil-Ortega M, Aranguez I, Souza D, Dreifaldt M, Somoza B, Dashwood MR.Br J Pharmacol. 2017 Oct;174(20):3561-3572.
Perivascular adipose tissue (PVAT) releases numerous factors and adipokines with paracrine effects on both vascular structure and function. These effects are variable as they depend on regional differences in PVAT among blood vessels and vary with changes in adiposity. There is considerable evidence demonstrating an association between coronary PVAT and the development and progression of coronary artery disease, which is associated with inflammation, oxidative stress, angiogenesis, vascular remodelling and blood clotting. However, PVAT also has a protective role in vascular grafts, especially the no-touch saphenous vein, in patients undergoing coronary artery bypass. This beneficial influence of PVAT involves factors such as adipocyte-derived relaxing factor, nitric oxide (NO), leptin, adiponectin, prostanoids, hydrogen sulphide and neurotransmitters, as well as mechanical protection. This article aims to highlight and compare the dual role of PVAT in the development and progression of coronary atherosclerosis, as well as in increased graft patency. Different deleterious and protective mechanisms of PVAT are also discussed and the inside-outside signalling paradigm of atherosclerosis development re-evaluated. The bidirectional communication between the arterial and venous wall and their surrounding PVAT, where signals originating from the vascular wall or lumen can affect PVAT phenotype, has been shown to be very complex. Moreover, signals from PVAT also influence the structure and function of the vascular wall in a paracrine manner.
- Long term effects of fetal undernutrition on rat heart. Role of hypertension and oxidative stress.
Rodríguez-Rodríguez P, López de Pablo AL, García-Prieto CF, Somoza B, Quintana-Villamandos B, Gómez de Diego JJ, Gutierrez-Arzapalo PY, Ramiro-Cortijo D, González MC, Arribas SM. PLoS One. 2017 Feb 17;12(2):e0171544.
Background and aims: Fetal undernutrition is a risk factor for heart disease in both genders, despite the protection of women against hypertension development. Using a rat model of maternal undernutrition (MUN) we aimed to assess possible sex differences in the development of cardiac alterations and the implication of hypertension and cardiac oxidative stress.
Methods: Male and female offspring from rats fed ad libitum (control) or with 50% of the normal daily intake during the second half of gestation (MUN) were used. Heart weight/body weight ratio (HW/BW), hemodynamic parameters (anaesthetized rats) and plasma brain natriuretic peptide (BNP, ELISA) were assessed in 21-day, 6-month and 22-month old rats. Plasma testosterone (ELISA) and cardiac protein expression of enzymes related to reactive oxygen species synthesis (p22phox, xanthine-oxidase) and degradation (catalase, Cu/Zn-SOD, Mn-SOD, Ec-SOD) were evaluated in 21-day and 6-month old rats (Western Blot). Heart structure and function was studied at the age of 22 months (echocardiography).
Results: At the age of 21 days MUN males exhibited significantly larger HW/BW and cardiac p22phox expression while females had reduced p22phox expression, compared to their respective sex-matched controls. At the age of 6-months, MUN males showed significantly larger blood pressure and cardiac xanthine-oxidase expression; MUN females were normotensive and had a lower cardiac expression of antioxidant enzymes, compared to their respective sex-matched controls. At the age of 22 months, both MUN males and females showed larger HW/BW and left ventricular mass and lower ejection fraction compared to sex-matched controls; only MUN males exhibited hypertension and a larger plasma BNP compared to aged male controls.
Conclusions: 1) During perinatal life females exposed to fetal undernutrition are protected from cardiac alterations, but in ageing they exhibit ventricular hypertrophy and functional loss, like MUN males; 2) cardiac oxidative stress might be implicated in the observed heart alterations in both sexes and 3) the severity of cardiac damage might be greater in males due to hypertension.