Mineralocorticoid Receptor and Leptin: A Dangerous Liaison in the Obese Heart

Multiple factors have been proposed as being responsible for cardiac damage in the context of obesity, including aldosterone/mineralocorticoid receptor and leptin. Aldosterone exerts proinflammatory, prooxidant and profibrotic actions, which can play a key role in the development of cardiac damage associated with different pathologies, through binding of mineralocorticoid receptor (MR). Moreover, its pharmacological blockade has demonstrated to improve these situations. Different studies have demonstrated that aldosterone is inappropriately elevated in obesity and MR antagonism improves left ventricle function and reduces circulating procollagen levels in patients with obesity without other comorbidities. Leptin is locally produced in the myocardium and its production is up-regulated in obesity. This adipokine is a proinflammatory, prooxidant and profibrotic factor that can participate in the cardiac damage associated with obesity. Interactions among leptin and aldosterone have previously been reported in different scenarios and at different levels, supporting a link between leptin and MR and that could result in the potentiation of the cardiac damage associated with obesity. Therefore, the aim of this review is to discuss whether MR activation can mediate the deleterious effects of leptin in the heart in the context of obesity, as well as the potential mechanisms involved in this process

Oxidative Stress in Obesity

Obesity is defined by the World Health Organization (WHO) as abnormal or excessive fat accumulation that presents a health risk [...

Fibrosis, the Bad Actor in Cardiorenal Syndromes: Mechanisms Involved

Cardiorenal syndrome is a term that defines the complex bidirectional nature of the interaction between cardiac and renal disease. It is well established that patients with kidney disease have higher incidence of cardiovascular comorbidities and that renal dysfunction is a significant threat to the prognosis of patients with cardiac disease. Fibrosis is a common characteristic of organ injury progression that has been proposed not only as a marker but also as an important driver of the pathophysiology of cardiorenal syndromes. Due to the relevance of fibrosis, its study might give insight into the mechanisms and targets that could potentially be modulated to prevent fibrosis development. The aim of this review was to summarize some of the pathophysiological pathways involved in the fibrotic damage seen in cardiorenal syndromes, such as inflammation, oxidative stress and endoplasmic reticulum stress, which are known to be triggers and mediators of fibrosis

Inflammation but Not Endothelial Dysfunction Is Associated with the Severity of Coronary Artery Disease in Dyslipidemic Subjects

Introduction. Endothelial dysfunction and inflammation play a key role in the development of atherosclerosis. The present study evaluated endothelial function, inflammatory parameters, and carotid intima-media thickness (IMT) in dyslipidemic patients with or without coronary artery disease (CAD). Methods. Metabolic profile and inflammatory parameters were determined in dyslipidemic patients with (+CAD, n = 33) and without (−CAD, n = 69) symptomatic CAD. Endothelial function was evaluated by flow mediated dilatation (FMD) and plasma concentration of nitrites and nitrates. Carotid IMT was measured by ultrasound. Results. No significant differences were observed in anthropometric hemodynamic or metabolic parameters between the groups. After adjusting by age and medication usage, some inflammatory markers were significantly higher in +CAD; however no significant differences in FMD or plasma levels of nitrites were observed. Conclusions. In subjects with dyslipidemia, the presence of CAD is associated with an elevation of certain inflammatory markers and carotid IMT but not with further endothelial dysfunction

Oxidative Stress and Vascular Damage in the Context of Obesity: The Hidden Guest

The vascular system plays a central role in the transport of cells, oxygen and nutrients between different regions of the body, depending on the needs, as well as of metabolic waste products for their elimination. While the structure of different components of the vascular system varies, these structures, especially those of main arteries and arterioles, can be affected by the presence of different cardiovascular risk factors, including obesity. This vascular remodeling is mainly characterized by a thickening of the media layer as a consequence of changes in smooth muscle cells or excessive fibrosis accumulation. These vascular changes associated with obesity can trigger functional alterations, with endothelial dysfunction and vascular stiffness being especially common features of obese vessels. These changes can also lead to impaired tissue perfusion that may affect multiple tissues and organs. In this review, we focus on the role played by perivascular adipose tissue, the activation of the renin-angiotensin-aldosterone system and endoplasmic reticulum stress in the vascular dysfunction associated with obesity. In addition, the participation of oxidative stress in this vascular damage, which can be produced in the perivascular adipose tissue as well as in other components of the vascular wall, is updated

Secreted phospholipase A2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: An inflammation–fibrosis link

Producción CientíficaSecreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.Ministerio de Economía, Industria y Competitividad (grants SAF2012-34460 and SAF2016-81063)Instituto de Salud Carlos III (grant PI18/010257729

Urocortin induces positive inotropic effect in rat heart

9 páginas, 6 figuras.Aims The aim of this study is to evaluate the positive inotropic effect of urocortin (Ucn) and to characterize its signalling pathways. Methods and results Contractility was measured in ex vivo Langendorff-perfused hearts isolated from Wistar rats. Isolated ventricular cardiomyocytes were used to analyse intracellular calcium ([Ca2+]i) transients evoked by electrical stimulation and L-type Ca2+ current by confocal microscopy and whole-cell patch-clamping, respectively. The application of Ucn to perfused hearts induced progressive, sustained, and potent inotropic and lusitropic effects that were dose-dependent with an EC50 of approximately 8 nM. Ucn effects were independent of protein kinase A (PKA) activation but were significantly reduced by protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) inhibitors and by brefeldin A, an antagonist of guanine nucleotide exchange factor, suggested to be an inhibitor of exchange protein activated by cAMP (Epac). These whole-organ effects were correlated with the inotropic effects observed in isolated cells: Ucn increased ICaL density, [Ca2+]i transients, cell shortening and Ca2+ content of sarcoplasmic reticulum. Conclusion Our results show that Ucn evokes potent positive inotropic and lusitropic effects mediated, at least in part, by an increase in ICaL and [Ca2+]i transient amplitude. These effects may involve the activation of Epac, PKC, and MAPK signalling pathways.This study was supported by ‘Red Cardiovascular RECAVA’ of Instituto Carlos III (grant number: RD06-0014-0020, RD06-0014-0007, PI06-0133), Consejerías de Salud, de Innovación Ciencia y Empresa de la Junta de Andalucía (grant numbers: 174/2006, P06-CTS-01711), Inserm, and by Agence Nationale pour la Recherche (grant: Physio2006Epac). T.S is a ‘Ramon y Cajal’ Researcher and E.C is a fellow student from RECAVA.Peer reviewe