Stéphane Schaak

Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1

AIMSnActivation of cardiac fibroblasts and their differentiation into myofibroblasts is a key event in the progression of cardiac fibrosis that leads to end-stage heart failure. Apelin, an adipocyte-derived factor, exhibits a number of cardioprotective properties; however, whether apelin is involved in cardiac fibroblast activation and myofibroblast formation remains unknown. The aim of this study was to determine the effects of apelin in activated cardiac fibroblasts, the potential related mechanisms and impact on cardiac fibrotic remodelling process.nnnMETHODS AND RESULTSnIn vitro experiments were performed in mouse cardiac fibroblasts obtained from normal and pressure-overload hearts. Pretreatment of naive cardiac fibroblasts with apelin (1-100 nM) inhibited Transforming growth factor-β (TGF-β)-mediated expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and collagen production. Furthermore, apelin decreased the spontaneous collagen production in cardiac fibroblasts isolated from hearts after aortic banding. Knockdown strategy and pharmacological inhibition revealed that prevention of collagen accumulation by apelin was mediated by a reduction in sphingosine kinase 1 (SphK1) activity. In vivo studies using the aortic banding model indicated that pretreatment with apelin attenuated the development of myocardial fibrotic remodelling and inhibited cardiac SphK1 activity and α-SMA expression. Moreover, administration of apelin 2 weeks after aortic banding prevented cardiac remodelling by inhibiting myocyte hypertrophy, cardiac fibrosis, and ventricular dysfunction.nnnCONCLUSIONnOur data provide the first evidence that apelin inhibits TGF-β-stimulated activation of cardiac fibroblasts through a SphK1-dependent mechanism. We also demonstrated that the administration of apelin during the phase of reactive fibrosis prevents structural remodelling of the myocardium and ventricular dysfunction. These findings may have important implications for designing future therapies for myocardial performance during fibrotic remodelling, affecting the clinical management of patients with progressive heart failure.

Morphologic and functional renal impact of acute kidney injury after prolonged hemorrhagic shock in mice.

Objective:Sparse data are available on renal consequences of hemorrhagic shock in mice. This study aimed to extend the current knowledge on functional and morphologic renal impact of hemorrhagic shock in mice and to determine its ability to stand as an accurate model of acute kidney injury. Design:In vivo study. Setting:University research unit. Subjects:C57/Bl6 mice. Interventions:A model of controlled hemorrhagic shock was adapted to determine the renal impact of hemorrhagic shock in mice. Measurements and Main Results:Renal functions and kidney morphology were followed up from 3 hrs to 21 days after hemorrhagic shock. When prolonged up to 2 hrs, hypotension (35 mm Hg mean arterial blood pressure) induced by temporary blood removal was responsible for an early and lasting increase in hypoxia-inducible factor-1&agr; and kidney-inducible molecule-1 gene expression that paralleled acute tubular necrosis and renal failure. Two-hr hypotension induced an important but reversible decrease in glomerular filtration rate up to 6 days after hemorrhagic shock. Other renal dysfunctions included a renal loss of sodium, assessed by the increase in sodium excretion, and a decrease in urine concentration that persists up to day 21. Tissular damages prevailed in the outer medulla 2 days after hemorrhagic shock, being maximal at day 6. At day 21, renal healing was associated with epithelial recovery and a significant interstitial fibrosis. Conclusions:Our data indicate that apparent recovery of renal function after acute kidney injury can mask persisting dysfunctions and tissular damages that could predispose to chronic kidney disease. Prolonged hemorrhagic shock in mice closely mimics renal effects induced by similar situation in humans, thus providing a useful tool to investigate pathophysiological mechanisms and protection strategies against acute kidney injury in situations such as hemorrhagic shock.

Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice

Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Genetic variation of human adrenergic receptors: from molecular and functional properties to clinical and pharmacogenetic implications.

Adrenergic receptors (ARs) are directly or indirectly involved in the control of a large panel of physiological functions and are the targets of drugs for the treatment of several common diseases including congestive heart failure, asthma or benign prostatic hyperplasia. The genotyping of human populations with diverse ethnicity has revealed that the genes encoding alpha(1A)-, alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)- and beta(3)-AR are polymorphic in their coding region as well as in their regulatory domains and non-coding regions. The functional consequences of these genetic variations include changes in expression at transcriptional or translational level, modification of coupling to heterotrimeric G-proteins resulting in a gain or a loss in function, and alteration of GRK-mediated receptor phosphorylation/desensitization or of agonist-promoted down-regulation. None of the mutations identified so far is per se a major risk factor for acquired or inherited disease; however, variants of alpha(2C)-AR and beta(1)-AR may act in synergy to determine the progression of heart failure and certain combinations of polymorphisms on beta(2)-AR correlate with asthmatic phenotypes or response to beta(2)-agonist therapy. Herein we summarize the present knowledge on AR gene polymorphisms, and discuss the putative consequences of variations resulting in receptor malfunction on pharmacogenomics and disease predisposition.