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Gomez-Hurtado N.,Complutense University of Madrid | Fernandez-Velasco M.,Institute Investigacion Hospital La Paz | Fernandez-Alfonso M.S.,Complutense University of Madrid | Bosca L.,Institute Investigaciones Biomedicas Alberto Sols Centro Mixto CSIC UAM | And 2 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2014

Circulating leptin levels are elevated in obesity and hyperleptinaemia has been postulated to be an independent risk factor for the development of cardiovascular diseases. Although many studies have been published on the mechanisms involved in the effects of leptin on cardiac function and pathological remodeling, scarce information is currently available analyzing the influence of prolonged leptin treatment on ionic cardiac channels remodeling in adult ventricular myocytes. Enzymatically isolated adult rat ventricular myocytes were treated with leptin or vehicle for 48h. Real-Time RT-PCR were used to analyze mRNA expression of Kir2.1, Cav1.2, Cav 3.1, Kv4.2 and Kv4.3 α-subunits and KChIP2 auxiliary subunit. The fast transient outward potassium channels (Itof) α-subunits Kv4.2, Kv4.3 and KChIP2 were analyzed by Western-blot. The fast transient outward potassium current and the action potentials were recorded in isolated myocytes by the whole-cell patch-clamp technique. Leptin treatment induced an up-regulation of Kv4.2, Kv4.3 and KChIP2 subunits mRNA expression. However, transcriptional levels of Kir2.1, Cav1.2, or Cav3.1 α-subunit channels were unmodified by leptin. Protein expression levels of Kv4.2, Kv4.3 and KChIP2 subunits were also increased by leptin. The electrophysiological study showed that leptin increases the fast transient outward potassium current amplitudes and densities shortening action potential duration. In addition, leptin activated Akt signaling in cardiomyocytes and this mechanism was involved in the effect of leptin on I tof channels. In conclusión, leptin increases both the expression and function of Itof channels in adult ventricular myocytes and this mechanism involves Akt signaling. Altogether these data suggest that leptin could exert beneficial or detrimental effects depending on the initial ventricular myocyte repolarizing reserve. © 2013 Springer-Verlag. Source

Fernandez-Velasco M.,Institute Investigacion Hospital La Paz | Fernandez-Velasco M.,Institute Investigaciones Biomedicas Alberto Sols | Prieto P.,Institute Investigaciones Biomedicas Alberto Sols | Terron V.,Institute Investigaciones Biomedicas Alberto Sols | And 14 more authors.
PLoS ONE | Year: 2012

The innate immune system is responsible for the initial response of an organism to potentially harmful stressors, pathogens or tissue injury, and accordingly plays an essential role in the pathogenesis of many inflammatory processes, including some cardiovascular diseases. Toll like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLRs) are pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. There is a line of evidence supporting that activation of TLRs contributes to the development and progression of cardiovascular diseases but less is known regarding the role of NLRs. Here we demonstrate the presence of the NLR member NOD1 (nucleotide-binding oligomerization domain containing 1) in the murine heart. Activation of NOD1 with the specific agonist C12-iEDAP, but not with the inactive analogue iE-Lys, induces a time- and dose-dependent cardiac dysfunction that occurs concomitantly with cardiac fibrosis and apoptosis. The administration of iEDAP promotes the activation of the NF-κB and TGF-β pathways and induces apoptosis in whole hearts. At the cellular level, both native cardiomyocytes and cardiac fibroblasts expressed NOD1. The NLR activation in cardiomyocytes was associated with NF-κB activation and induction of apoptosis. NOD1 stimulation in fibroblasts was linked to NF-κB activation and to increased expression of pro-fibrotic mediators. The down-regulation of NOD1 by specific siRNAs blunted the effect of iEDAP on the pro-fibrotic TGF-β pathway and cell apoptosis. In conclusion, our report uncovers a new pro-inflammatory target that is expressed in the heart, NOD1. The specific activation of this NLR induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis, pathological processes involved in several cardiac diseases such as heart failure. © 2012 Fernández-Velasco et al. Source

Ruiz-Hurtado G.,University Paris - Sud | Dominguez-Rodriguez A.,University Paris - Sud | Pereira L.,University of California at Davis | Fernandez-Velasco M.,Institute Investigacion Hospital La Paz | And 4 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2012

Cardiac actions of Epac (exchange protein directly activated by cAMP) are not completely elucidated. Epac induces cardiomyocytes hypertrophy, Ca2+/calmodulin protein kinase II (CaMKII) and excitation-transcription coupling in rat cardiac myocytes. Here we aimed to elucidate the pathway cascade involved in Epac sustained actions, as during the initiation of hypertrophy development, where β-adrenergic signaling is chronically stimulated. Rats were treated with the Epac selective activator 8-pCPT during 4weeks and Ca2+ signaling was analyzed in isolated cardiac myocytes by confocal microscopy. We observed a positive inotropic effect manifested by increased [Ca2+]i transient amplitudes. In order to further analyze these actions, we incubated adult cardiomyocytes in the presence of 8-pCPT. The effects were similar to those obtained in-vivo and are blunted by Epac1 knock down. Interestingly, the increase in [Ca2+] transients was abolished by protein synthesis blockade or when the downstream effectors of calmodulin (CaMKII or calcineurin) were inhibited, pointing to calmodulin (CaM) as an important downstream protein in Epac sustained actions. In fact, CaM expression was enhanced by 8-pCPT treatment in isolated cells, as found by Western blots. Moreover, the 8-pCPT-induced, PKA-independent, positive inotropic effect was favored by enhanced extracellular Ca2+ influx via L-type Ca2+ channels. However, 8-pCPT also induced aberrant Ca2+ release as Ca2+ waves and extra [Ca2+]i transients, suggesting proarrhythmic effect. These results provide new insights regarding Epac cardiac actions, suggesting an important role in the initial compensation of the heart to pathological stimuli during the initiation of cardiac hypertrophy, favoring contraction but also arrhythmia risk. © 2012 Elsevier Ltd. Source

Garcia-Hoz C.,Autonomous University of Madrid | Garcia-Hoz C.,Institute Investigacion Sanitaria La Princesa | Sanchez-Fernandez G.,Autonomous University of Madrid | Sanchez-Fernandez G.,Institute Investigacion Sanitaria La Princesa | And 14 more authors.
Journal of Biological Chemistry | Year: 2012

Gq-coupled G protein-coupled receptors (GPCRs) mediate the actions of a variety of messengers that are key regulators of cardiovascular function. Enhanced Gα q-mediated signaling plays an important role in cardiac hypertrophy and in the transition to heart failure. We have recently described that Gα q acts as an adaptor protein that facilitates PKCζ-mediated activation of ERK5 in epithelial cells. Because the ERK5 cascade is known to be involved in cardiac hypertrophy, we have investigated the potential relevance of this pathway in cardiovascular Gq-dependent signaling using both cultured cardiac cell types and chronic administration of angiotensin II in mice. We find that PKCζ is required for the activation of the ERK5 pathway by Gq-coupled GPCRin neonatal and adult murine cardiomyocyte cultures and in cardiac fibroblasts. Stimulation of ERK5 by angiotensin II is blocked upon pharmacological inhibition or siRNA-mediated silencing of PKCζ in primary cultures of cardiac cells and in neonatal cardiomyocytes isolated from PKCζ-deficient mice. Moreover, upon chronic challenge with angiotensin II, these mice fail to promote the changes in the ERK5 pathway, in gene expression patterns, and in hypertrophic markers observed in wild-type animals. Taken together, our results show that PKCζ is essential for Gq-dependent ERK5 activation in cardiomyocytes and cardiac fibroblasts and indicate a key cardiac physiological role for the Gα q/PKCζ/ERK5 signaling axis. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Sanchez-Martinez M.,Autonomous University of Madrid | Sanchez-Martinez M.,Catholic University of Avila | Sanchez-Martinez M.,Institute Investigacion Hospital La Paz | Castell M.V.,Autonomous University of Madrid | And 10 more authors.
European Geriatric Medicine | Year: 2016

Objectives: The aim of this study is to identify transitions in the functional status (FS) of older adults and to assess the influence of physical performance, depression, and cognitive impairment at baseline, and their changes over time, on FS decline. Methods: This is a population-based cohort with 4 years of follow-up (2008-2011) in "Peñagrande cohort" (Madrid) in Primary care centres, composed of 607 persons aged ≥ 65 years. Transition in FS was classified as no disability, mobility disability and activities of daily living disability based on FS in 2008 and 2011. FS decline was considered as transition to decline, continued disability or death. The Short physical performance battery (SPPB), gait speed (GS), depression and cognitive impairment at baseline and as time-dependent variables (TDVs), were the principal independent variables in logistic regression analysis. Results: Some 43.3% (95% CI: 39.3-47.4) of the study population experienced FS decline. Low SPPB and depression at baseline were associated with FS decline (odds ratio [OR] 5.79, 95% CI: 3.39-9.90 and OR 2.92, 95% CI: 1.71-5.02, respectively). The OR of FS decline (fully adjusted) were: 2.90 (95% CI: 1.59-5.29) for decrease in SPPB over time, 5.73 (95% CI: 3.36-9.77) for worsening depression, and 1.93 (95% CI: 1.13-3.29) for worsening of cognitive impairment. GS was also associated with FS decline when used as an alternative indicator of physical performance both at baseline (OR 3.26 [95% CI: 2.08-5.11]) and as TDV (OR 5.60 [95% CI: 3.17-9.89]). Conclusion: The presence of low physical performance, depression and cognitive impairment predicts FS decline. Evaluation of these factors could be helpful in early diagnosis of FS decline. © 2016 Elsevier Masson SAS and European Union Geriatric Medicine Society. Source

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