Browsing by Author "González, María del Carmen"

Leptin causes vasodilatation both by endothelium-dependent and-independent mechanisms. Leptin is synthesized by perivascular adipose tissue (PVAT). The hypothesis of this study is that a decrease of leptin production in PVAT of spontaneously hypertensive rats (SHR) might contribute to adiminished paracrine anticontractile effect of the hormone. We have determined in aorta from Wistar-Kyoto (WKY) and SHR leptin mRNA and protein levels in PVAT, the effect of leptin and PVAT on contractile responses, and leptin-induced relaxation and nitricoxide (NO) production. Leptin mRNA and protein expression were significantly lower in PVAT from SHR. Concentration response curves to angiotensin II were significantly blunted in presence of PVAT as well as by exogenousleptin (10−9M) only in WKY. This anticontractile effect was endothelium-dependent. Vasodilatation induced by leptin was smaller in SHR than in WKY, and was also endothelium-dependent. More over, release of endothelial NO in response to acute leptin was higherin WKY compared to SHR, but completely abolished in the absence of endothelium. In conclusion, the reduced anticontractile effect of PVAT in SHR might be attributed to a reduced PVAT-derived leptin and to an abrogated effect of leptin on endothelial NO release probably due to an impaired activation of endothelial NO synthase

The aim of this study was to characterize alterations in vascular structure and mechanics in murine mesenteric arteries from obese non-hypertensive mice, as well as their relationship with adipokines. Four-week old C57BL/6J male mice were assigned either to a control (C, 10% kcal from fat) or a high-fat diet (HFD, 45% kcal from fat) for 32 weeks. HFD animals weighed 30% more than controls (p b 0.001), exhibited similar blood pressure, increased leptin, insulin and superoxide anion (O2 •−) levels, and reduced adiponectin levels and nitric oxide (NO) bioavailability. Arterial structure showed an outward remodeling with an increase in total number of both adventitial and smoothmuscle cells inHFD.Moreover, HFDmice exhibited an increased arterial stiffness assessed by β-values (C=2.4±0.5 vs HFD=5.3±0.8; p b 0.05) and aortic pulse wave velocity (PWV, C=3.4±0.1 vs HFD = 3.9 ± 0.1; p b 0.05). β-Values and PWV positively correlated with leptin, insulin or O2 •− levels, whereas they negatively correlated with adiponectin levels and NO bioavailability (p b 0.01). A reduction in fenestrae number together with an increase in type-I collagen amount (p b 0.05) were observed in HFD. These data demonstrate that HFD accounts for the development of vascular remodeling and arterial stiffness associated with adipokine dysregulation and oxidative stress, independently of hypertension development.

The Munich Wistar Frömter (MWF) rat strain represents an experimental model to study cardiovascular alterations under conditions of progressive albuminuria. The aim of this study was to evaluate the association between genetic predisposition to albuminuria and the development of arterial stiffness and/or vascular remodelling. Experiments were performed in mesenteric arteries from 12-week-old MWF, Wistar Kyoto (WKY) and consomic MWF-6SHR and MWF-8SHR rats in which chromosomes 6 or 8 associated with albuminuria from MWF were replaced by the respective chromosome from spontaneously hypertensive rats (SHR). Incremental distensibility, wall stress and strain were reduced, and arterial stiffness was significantly increased in albuminuric MWF compared with WKY. Albuminuria suppression in both consomic strains was associated with lower β-values in MWF-8SHR and MWF-6SHR compared with MWF. Moreover, elastin content was significantly lower in MWF external elastic lamina compared with WKY and both consomic strains. In addition, a reduction in arterial external and internal diameter and cross-sectional area was detected in MWF compared with WKY, thus exhibiting an inward hypotrophic remodelling. However, these alterations remained unchanged in both consomic strains. These data demonstrate that albuminuria in MWF is associated with increased arterial stiffness due to a reduction of elastin content in the external elastic lamina. Moreover, inward hypotrophic remodelling in MWF is not directly associated with albuminuria. In contrast, we demonstrated that two major genetic loci affect both the development of albuminuria and arterial stiffness, thus linking albuminuria and impairment of mechanical properties of resistance arteries.

Fibrates are peroxisome proliferator-activated receptor alpha (PPARa) ligands used to normalize lipid and glucose parameters and exert anti-inflammatory effects. The acute-phase response (APR) is an important inflammatory process. One of the most important acute-phase proteins in rats is a2-macroglobulin (A2Mg). Whereas normal adult rats present low serum levels, pregnant rats display high amounts. Therefore, we used pregnant rats to detect the effect of fenofibrate on hepatic A2Mg expression by RT-PCR and Northern blot. Virgin rats were used as controls. The expression of other APR genes, a known fibrate-responder gene, gamma-chain fibrinogen (g-Fib), and one gene from the same family as A2Mg, complement component 3 (C3), were also measured in liver. In order to determine whether the fibrateeffects were mediated by PPARa, wild-type mice and PPARa-null mice were also used and treated with WY-14,643 (WY) or di-2-ethylhexyl phthalate (DEHP). Fenofibrate depressed A2Mg expression in virgin rats, but expression was decreased more sharply in pregnant rats. Expression of C3 and g-Fib was diminished after treatment only in pregnant rats. On the other hand, WY, but not DEHP, reduced A2Mg and g-Fib expression in the livers of wild-type mice, without any effect in PPARa-null mice. WY or DEHP did not affect C3 expression. Therefore, A2Mg expression is modified by PPARa agonists not only in pregnant rats under augmented APR protein synthesis, but also in virgin rats and mice under basal conditions. Interestingly, our results also identify A2Mg as a novel PPARa agonist-regulated gene.

Peroxisome proliferator-activated receptor alpha (PPARa) binds fatty acids, eicosanoids, or fibrates, and regulates transcription of specific genes. These genes are involved both in lipid and glucose metabolism as well as in cellular differentiation and inflammation. Thus, PPARa controls metabolic and inflammatory disturbances and therefore, its activation is expected to normalize lipid and glucose parameters and exert anti-inflammatory effects. In/act, PPARa agonists have already been demonstrated to benefit metabolic syndrome, type 2 diabetes and cardiovascular diseases. However, several findings have revealed either potential adverse effects or unefficient hypolipidemic action of PPARa activation, highlighting the need to search for pharmacological or nutritional solutions based on modulation of PPARa This strategy could be either complementary to or replace the classical therapy. Thus, compounds that selectively and/or specifically modulate PPARa activity appear to be a promising alternative.

Dietary treatment with high-fat diets (HFD) triggeenrs diabetes and hyperleptinemia, con- comitantly with a partial state of leptin resistance that affects hepatic and adipose tissue but not the heart. In this context, characterized by widespread steatosis, cardiac lipid con- tent remains unchanged. As previously reported, HFD-evoked hyperleptinemia could be a pivotal element contributing to increase fatty-acid (FA) metabolism in the heart and to prevent cardiac steatosis. This metabolic adaptation might theoretically reduce energy efficiency in cardiomyocytes and lead to cardiac electrophysiological remodeling. There- fore the aim of the current study has been to investigate the impact of long-term HFD on cardiac metabolism and electrophysiological properties of the principal ionic currents responsible of the action potential duration in mouse cardiomyocytes. Male C57BL/6J mice were fed a control (10 kcal% from fat) or HFD (45 kcal% from fat) during 32 weeks. Quantification of enzymatic activities regulating mitochondrial uptake of pyruvate and FA showed an increase of both carnitine-palmitoyltransferase and citrate synthase activities together with a decrease of lactate dehydrogenase and pyruvate dehydrogenase activities. Increased expression of uncoupling protein-3, Mn-, and Cu/Zn-superoxide dismutases and catalase were also detected. Total glutathione/oxidized glutathione ratios were unaffected by HFD. These data suggest that HFD triggers adaptive mechanisms aimed at facilitating FA catabolism, and preventing oxidative stress. All these changes did not affect the dura- tion of action potentials in cardiomyocytes and only slightly modified electrocardiographic parameters.

Fetal undernutrition programs cardiometabolic diseases, with higher susceptibility in males. The mechanisms implicated are not fully understood and may be related to sex differences in placental adaptation. To evaluate this hypothesis, we investigated placental oxidative balance, vascularization, glucocorticoid barrier, and fetal growth in rats exposed to 50% global nutrient restriction from gestation day 11 (MUN, n = 8) and controls (n = 8). At gestation day 20 (G20), we analyzed maternal, placental, and fetal weights; oxidative damage, antioxidants, corticosterone, and PlGF (placental growth factor, spectrophotometry); and VEGF (vascular endothelial growth factor), 11 -HSD2, p22phox, XO, SOD1, SOD2, SOD3, catalase, and UCP2 expression (Western blot). Compared with controls, MUN dams exhibited lower weight and plasma proteins and higher corticosterone and catalase without oxidative damage. Control male fetuses were larger than female fetuses. MUN males had higher plasma corticosterone and were smaller than control males, but had similar weight than MUN females. MUN male placenta showed higher XO and lower 11 - HSD2, VEGF, SOD2, catalase, UCP2, and feto-placental ratio than controls. MUN females had similar feto-placental ratio and plasma corticosterone than controls. Female placenta expressed lower XO, 11 -HSD2, and SOD3; similar VEGF, SOD1, SOD2, and UCP2; and higher catalase than controls, being 11 -HSD2 and VEGF higher compared to MUN males. Male placenta has worse adaptation to undernutrition with lower efficiency, associated with oxidative disbalance and reduced vascularization and glucocorticoid barrier. Glucocorticoids and low nutrients may both contribute to programming in MUN males.

To investigate the response to fenofibrate in pregnant rats, 0 mg, 100 mg or 200 mg of fenofibrate per kilogram body weight oral doses were given twice a day from day 16 of gestation and studied at day 20. Virgin rats were studied in parallel. Whereas in pregnant rats plasma triglycerides significantly increased, in virgin rats, fenofibrate decreased plasma triglycerides which accumulated in liver. Fenofibrate faithfully modulated the hepatic expression of PPARa responsive genes. Fenofibrate increased mRNA contents corresponding to both acyl-CoA oxidase, carnitine palmitoyltransferase (CPT), and peroxisome proliferatoractivated receptor alpha (PPAR), and lowered mRNA amounts of apolipoproteins B and C-III, both in virgin and pregnant rats. However, genes related to hepatic lipogenesis, such as PPARy and stearoyl-CoA desaturase (SCD), showed an augmented expression by fenofibrate in virgin rats, but not in pregnant animals. We propose that the opposite effects of fenofibrate treatment in virgin and pregnant rats are a consequence of the enhanced capability for VLDL-triglyceride production in the latter, further promoted by the elevated amount of free fatty acids (FFA), which reach the liver in treated pregnant rats and were not sufficiently oxidized and/or stored, and therefore would have to be canalized as triglycerides to the plasma. Thus, the present study shows how fenofibrate, in spite of efficiently exerting its expected molecular effects in the liver (i.e., to induce fatty acid and lipoprotein catabolism, and to reduce TG-rich lipoprotein secretion), was unable to reverse the typical hypertriglyceridaemia of gestation.