Claude Delcayre

Paris Diderot University, Lutetia Parisorum, Île-de-France, France

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Publications (118)587.54 Total impact

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    ABSTRACT: Experimentally, aldosterone in association with NaCl induces cardiac fibrosis, oxidative stress, and inflammation through mineralocorticoid receptor activation; however, the biological processes regulated by aldosterone alone in the heart remain to be identified. Mice were treated for 7 days with aldosterone, and then cardiac transcriptome was analyzed. Aldosterone regulated 60 transcripts (51 upregulated and 9 downregulated) in the heart (fold change ≥1.5, false discovery rate <0.01). To identify the biological processes modulated by aldosterone, a gene ontology analysis was performed. The majority of aldosterone-regulated genes were involved in cell division. The cardiac Ki-67 index (an index of proliferation) of aldosterone-treated mice was higher than that of nontreated mice, confirming microarray predictions. Costaining of Ki-67 with vinculin, CD68, α-smooth muscle actin, CD31, or caveolin 1 revealed that the cycling cells were essentially endothelial cells. Aldosterone-induced mineralocorticoid receptor-dependent proliferation was confirmed ex vivo in human endothelial cells. Moreover, pharmacological-specific blockade of mineralocorticoid receptor by eplerenone inhibited endothelial cell proliferation in a preclinical model of heart failure (transverse aortic constriction). Aldosterone modulates cardiac gene expression and induces the proliferation of cardiac endothelial cells in vivo. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Full-text · Article · Dec 2015 · Journal of the American Heart Association
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    ABSTRACT: Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin [MCP]), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (-20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P<0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). After isoproterenol, Gal-3 gene expression (P<0.05 versus placebo) and protein levels (-61% and -69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.
    No preview · Article · Mar 2015 · Journal of the American College of Cardiology
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    ABSTRACT: Angiotensin II and aldosterone have both beneficial and deleterious effects that affect the function of cardiovascular system (blood vessels and heart), the kidneys and other organs. The history of the discoveries of Angiotensin II and aldosterone, and of the molecules that inhibit their synthesis or antagonize their receptors, is an excellent example of translational research. Indeed, a series of experiments have been determinant to initiate clinical studies, and conversely, some unexpected secondary effects observed in treated patients have been understood by experimental research. This chapter will describe the functions of the renin-angiotensin-aldosterone system and the progression of ideas which have allowed to introduce some of the most successful drugs used in hypertension and heart failure.
    No preview · Chapter · Jan 2015
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    L Fazal · E Polidano · R Merval · G Coutance · C Delcayre · Jl Samuel
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    ABSTRACT: Introduction: Scarcity of microvessels and deregulation of the renin-angiotensin-aldosterone system contribute to the development of heart failure in diabetes. We showed that cardiac aldosteronism inhibits the onset of cardiomyopathy in type 1 diabetic mice by preventing capillary rarefaction (Messaoudi, 2009). Another promising therapeutic approach to prevent diabetic heart disease is exercise training (Ex). Exercise is beneficial in diabetic cardiomyopathy in human and experimentally. Thus, the objective of the study was to determine whether cardiac aldosterone-induced angiogenesis in type 2 diabetes (D) is used to meet the energy demand associated with Ex, and to identify the mechanisms involved. Methods: 3 weeks old mice overexpressing cardiac aldosterone system (AS) and their controls (WT) were made diabetic by enriched fat and sucrose diet. After 4 months of diet, diabetic mice and their controls were subjected to 2 months of Ex on treadmill (3 sessions/week). Results: Cardiac function was not affected by Ex. The Ex led to cardiac hypertrophy in AS-D-Ex mice (+15 % in AS-D-Ex vs AS-D, P<0.01) while it improved the basic parameters of WT-D-Ex vs WT-D (body weight: -15 %, blood glucose: -15%, resistance to insulin:-50%). Interestingly, the Ex revealed a defect in AS mice: the cumulative distance traveled by AS mice, with or without type 2 D was 30% lower than in WT mice (p < 0.01). In addition, a 75% mortality was observed in AS mice (diabetic or not) submitted to the Ex, in contrast to WT mice. These results demonstrate that AS mice, unfit to Ex, developed a pathological hypertrophy. In contrast to the observed baseline responses, the Ex did not phosphorylate and thus did not activated the Akt pathway in AS-D-Ex mice (NS vs AS-D), signing the absence of activation of the physiological pathway of cardiac hypertrophy. Conclusion: These results demonstrate a deleterious effect of cardiac aldosteronism in response to Ex, regardless of diabetic context, thus underlining that the microangiogenesis observed in the AS-D mice prevented neither the inability to Ex nor mortality. This suggests that the proangiogenic effect of cardiac hyperaldosteronism associated with type 2 diabetes is not enough to cope with this overload of cardiac output associated with the physical exercise.
    Preview · Article · Jul 2014 · Cardiovascular Research
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    ABSTRACT: Notch3, a receptor expressed in vascular smooth muscle cells (VSMC) and pericytes, has a key role in the integrity of resistance arteries by controlling the maturation of VSMC and the arterial differentiation. The goal of the study was to decipher the role of Notch3 in the normal heart and in the response to pressure overload. To reach our objectives, we used adult male C57Bl/6J mice lacking expression of the Notch3 gene (N3-/-). Hypertension was induced by continuous infusion of Angiotensin II (AngII) for 28 days (1μg/kg/min) in WT and N3-/- mice (n>13). The analysis combined with echocardiography analysis, mRNA quantification, western-blot, immuno- and/or histo-morphometry. In basal conditions, N3-/- mice exhibited cardiac hypertrophy (+20%, p<0.001 vs Wild Type, WT) combined with defects at the structure of coronary artery as evidenced by decreased F-actin content in the media (-20%, p<0.05) and decreased density of arterioles (p<0.05). The AngII -induced Hypertension is lower inN3-/- mice (-20%, p<0.05 vs WT +AngII). Despite this blunted systemic effect, N3-/- mice developed a more severe heart failure (HF) compared to WT+AngII mice with lower shortening fraction (-20%, p<0.01), higher cardiac hypertrophy (+35%, p<0.05), and enhanced markers of fibrosis and inflammation [induction of galectin-3 (x3.5, p<0.01)]. The results in N3-/- +AngII mice, which combined the induction of Angiopoïetin 2 mRNA (+70%, p<0.05) and the repression of VEGFa (p<0.05) are in favour of coronary artery destabilization. Interestingly, coronary vessels did not show medial hypertrophy and this lack of adaptive response to hypertension was accompanied by a decreased expression of F-actin and SM actin mRNA (-50%, p<0.01). Moreover a treatment by Notch3 antisens oligonucleotides (ON) of WT +AngII mice impair coronary artery network as suggested by Angiopoïetin 2 induction (p<0.05 vs WT+AngII+ scrambled ON). Altogether, we provide lines of evidence that alterations of Notch3 signaling pathway in the coronary arteries might play a role in the occurrence of HF in response to chronic increase in blood pressure.
    Full-text · Article · Jul 2014 · Cardiovascular Research
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    ABSTRACT: This research investigated the impact of angiotensin AT1 receptor (Agtr1) blockade on left ventricular (LV) hypertrophy in a mouse model of human hypertrophic cardiomyopathy (HCM), which carries one functional allele of Mybpc3 gene coding cardiac myosin-binding protein C (cMyBP-C). Five-month-old heterozygous cMyBP-C knockout (Het-KO) and wild-type mice were treated with irbesartan (50 mg/kg/day) or vehicle for 8 weeks. Arterial blood pressure was measured by tail cuff plethysmography. LV dimension and function were accessed by echocardiography. Myocardial gene expression was evaluated using RT-qPCR. Compared with wild-type littermates, Het-KO mice had greater LV/body weight ratio (4.0 ± 0.1 vs. 3.3 ± 0.1 mg/g, P < 0.001), thicker interventricular septal wall (0.70 ± 0.02 vs. 0.65 ± 0.01 mm, P < 0.02), lower Mybpc3 mRNA level (-43%, P < 0.02), higher four-and-a-half LIM domains 1 (Fhl1, +110%, P < 0.01), and angiotensin-converting enzyme 1 (Ace1, +67%, P < 0.05), but unchanged Agtr1 mRNA levels in the septum. Treatment with irbesartan had no effect in wild-type mice but abolished septum-predominant LV hypertrophy and Fhl1 upregulation without changes in Ace1 but with an increased Agtr1 (+42%) in Het-KO mice. Thus, septum-predominant LV hypertrophy in Het-KO mice is combined with higher Fhl1 expression, which can be abolished by AT1 receptor blockade, indicating a role of the renin-angiotensin system and Fhl1 in cMyBP-C-related HCM.
    Full-text · Article · Jun 2014 · Fundamental and Clinical Pharmacology
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    ABSTRACT: Purpose: Studies have shown that aldosterone would have angiogenic effects, and therefore would be beneficial in the context of cardiovascular diseases. We thus investigated the potential involvement of aldosterone in triggering a cardiac angiogenic response in the context of type-2 diabetes, and the molecular pathways involved. Procedure: 3 week-old male mice, overexpressing aldosterone-synthase (AS), and their controls littermates (WT) were fed with a standard or high fat, high sucrose (HFHS) diet. After 6 months of diet, mice were sacrificed and cardiac samples were assayed by RT-PCR, immuno-blotting and -histology. Findings: HFHS-diet induced type-2 diabetes (D) in WT and AS mice. VEGFa mRNAs were decreased in WT-D (-43%, P<0.05 vs. WT) while increased in AS-D mice (+236%, P<0.01 vs. WT-D). In WT-D hearts, the proapoptotic p38-MAPK was activated (P<0.05 vs. WT and AS-D) whereas Akt activity decreased. The AS-mice, that exhibited a cardiac upregulation of IGF1-R, showed an increase in Akt phosphorylation when diabetic (P<0.05 vs. WT and AS-D). Contrary to WT-D, AS-D hearts did not express inflammatory markers and exhibited a normal capillary density (P<0.05 vs. WT-D) Conclusions: To our knowledge, this is the first study providing new insights into the mechanisms whereby aldosterone prevents diabetes-induced cardiac disorders.
    Preview · Article · Feb 2014 · The FASEB Journal
  • L. Fazal · F. Azibani · J.-L. Samuel · C. Delcayre

    No preview · Article · Nov 2013 · Archives des Maladies du Coeur et des Vaisseaux - Pratique
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    ABSTRACT: The cardiovascular diseases are the leading causes of death in men and women in industrialised countries. While the impact of biological sex on cardiovascular pathophysiology has long been known, the sex-specific mechanisms mediating these processes have progressed during the last years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research but also with regards to therapeutic approaches.
    Preview · Article · Jun 2013 · British Journal of Pharmacology

  • No preview · Article · Jun 2013 · Fundamental and Clinical Pharmacology
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    ABSTRACT: Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results from cardiac transcriptomic changes induced by mechanical and hormonal factors. Angiotensin II and aldosterone often collaborate in pathological situations to induce hypertrophy of cardiomyocytes, vascular inflammation, perivascular and interstitial fibrosis, and microvascular rarefaction. Experimental models of transgenic mice overexpressing renin in liver, leading to increased plasma angiotensin II and severe hypertension, and mice overexpressing aldosterone-synthase in cardiomyocytes, leading to a doubling of intracardiac aldosterone concentration have shown that cardiac fibrosis in the heart depends on a balance between pro-fibrotic (TGF-ß, galectin-3) and anti-fibrotic (BNP, ANP) factors. Recent studies using cell-specific deletion of the mineralocorticoid receptor indicate that its activation in macrophages is a key step in the development of cardiac fibrosis in the setting of hemodynamic or hormonal challenges. This review focuses on the impact of inappropriate stimulation of aldosterone in the development of cardiac fibrosis.
    No preview · Article · May 2013 · Current Hypertension Reports
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    ABSTRACT: Inappropriate mineralocorticoid receptor (MR) activation is involved in cardiac diseases. Whether and how aldosterone is involved in the deleterious effects of cardiac mineralocorticoid activation is still unclear. Mice overexpressing MR in cardiomyocytes and their controls were treated for 7 days with aldosterone, and cardiac transcriptome was analyzed. Aldosterone regulated 265 genes in cardiomyocyte-targeted MR overexpression mice. Forty three of these genes were also differentially expressed between untreated cardiomyocyte-targeted MR overexpression and controls mice, thus representing putative aldosterone-regulated genes in cardiomyocytes. Among these genes, we focused on connective tissue growth factor (CTGF). In vivo, in cardiomyocyte-targeted MR overexpression mice, aldosterone (but not corticosterone) induced CTGF expression (mRNA and protein) in cardiomyocytes. Ex vivo, aldosterone induced the binding of mineralocorticoid receptor to CTGF promoter and increased the expression of its transcript. Aldosterone induction of CTGF synthesis in cardiomyocytes seems pathologically relevant as the increase in CTGF observed in a model of heart failure (transverse aortic constriction) in rats was prevented by eplerenone, a mineralocorticoid receptor blocker. This study demonstrates that aldosterone specifically regulates gene expression in cardiomyocytes despite large prevalence of glucocorticoids in plasma.
    Full-text · Article · Jan 2013 · Hypertension
  • Feriel Azibani · Claude Delcayre · Jane-lise Samuel
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    ABSTRACT: The cardiovascular diseases are the leading cause of death in men and women in industrialized countries. The profound impact of biological sex on cardiovascular physiology or pathology has long been known, but the biological mechanisms responsible for sex-related differences have emerged more recently. Hormone therapy replacement is classically used to prevent cardiovascular pathologies in postmenopausal women but more recently, the beneficial effect of exercise begins to be taken into account. This review aimed to focus on the respective impact of sexual hormones, and/or exercise on the adaptive response of the heart to pathological situations such as severe pressure overload.
    No preview · Chapter · Jan 2013

  • No preview · Article · Jan 2013
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    ABSTRACT: Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo.
    No preview · Article · Sep 2012 · Journal of neuroimmunology
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    ABSTRACT: : Aldosterone antagonists (AAs) have beneficial effects on ventricular histological and electrical remodeling and improve noradrenaline uptake. Adding an AA to a beta-blocker (BB) further improves cardiac mortality in heart failure patients. We investigated if adjunction of a BB modifies beneficial effects of spironolactone on different parameters of the ventricular remodeling. : A severe myocardial infarction (MI) was produced in rats. Three months after surgery, left ventricular (LV) function was assessed by echocardiography. Fifty-five rats with heart failure were then randomized in 5 groups: sham, MI, and MI treated for 4 weeks with spironolactone (10 mg·kg·d), atenolol (1 mg·kg·d), or both. Holter transducers were implanted to record 24-hour ventricular electrical parameters, mean cycle length (RR) and SD of RR. Before killing, invasive left ventricular end diastolic pressure (LVEDP) was recorded. LV samples were used for histological analysis and catecholamine assay. : Rats with MI had significantly increased LVEDP (32 ± 3 vs. 14 ± 1 mm Hg), LV, collagen content (5.8% ± 1.4% vs. 3.6% ± 0.7%), ventricular premature complexes (2.5 10 ± 10 vs. 30 ± 13), and decreased meanRR (164 ± 2 vs. 169 ± 1 milliseconds) and SDRR (3.9 ± 0.2 vs. 5.4 ± 0.2 milliseconds) compared with sham. At nonhypotensive doses, spironolactone and atenolol similarly improved LVEDP. Compared with MI, although spironolactone significantly decreased ventricular premature complexes, LV collagen and noradrenaline contents, and improved meanRR and SDRR, atenolol had effects only on meanRR and SDRR. Addition of atenolol to spironolactone further improved spironolactone effects on all these parameters. : AA improved, independently of the cardiac function, histological and electrical remodeling after MI. A BB added to an AA did not blunt these beneficial effects; furthermore, it improved these effects related to spironolactone.
    No preview · Article · Jun 2012 · Journal of cardiovascular pharmacology
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    ABSTRACT: Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results in cardiac transcriptomic changes induced by mechanical and hormonal factors (angiotensin II and aldosterone are the most important). The major features of cardiac remodeling are the hypertrophy of cardiomyocytes, interstitial and perivascular fibrosis, and microvascular rarefaction. Inappropriate stimulation of the renin-angiotensin-aldosterone system (RAAS) participates to the development of heart failure. The respective roles of angiotensin II and aldosterone in cardiac remodeling are poorly understood. The development of fibrosis in the heart depends of a balance between profibrotic (TGFβ, CTGF, inflammation) and antifibrotic (BNP, ANP, BMP4 and BMP7) factors. The profibrotic and proinflammatory effects of angiotensin II and aldosterone are very well demonstrated; however, their actions on antifibrotic factors expression are unknown. In order to explore this, we used RenTgKC mice overexpressing renin into the liver, leading to an increased plasma angiotensin II and thus induction of severe hypertension, and AS mice overexpressing aldosterone synthase (AS) in cardiomyocytes which have a doubled intracardiac aldosterone concentration. Male AS mice have a dysfunction of the coronary arteries relaxation without structural and functional changes of the myocardium. Mice derived from a crossing between the RenTgKC and AS strains were used in this work. It is shown that angiotensin II induces the expression of BNP and BMPs which ultimately slows the progression of myocardial fibrosis, and that aldosterone inhibits the expression of these factors and thus worsens the fibrosis.
    No preview · Article · Jun 2012 · Annales de cardiologie et d'angeiologie
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    ABSTRACT: Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of its transcriptional repressor Sox6. Thus, aldosterone inhibits the fetal program and increases cardiac hypertrophy in hypertensive mice.
    Full-text · Article · May 2012 · PLoS ONE
  • F Azibani · L Fazal · C Chatziantoniou · J-L Samuel · C Delcayre
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    ABSTRACT: Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results in cardiac transcriptomic changes induced by mechanical and hormonal factors (angiotensin II and aldosterone are the most important). The major features of cardiac remodeling are the hypertrophy of cardiomyocytes, interstitial and perivascular fibrosis, and microvascular rarefaction. Inappropriate stimulation of the renin-angiotensin-aldosterone system (RAAS) participates to the development of heart failure. The respective roles of angiotensin II and aldosterone in cardiac remodeling are poorly understood. The development of fibrosis in the heart depends of a balance between profibrotic (TGFβ, CTGF, inflammation) and antifibrotic (BNP, ANP, BMP4 and BMP7) factors. The profibrotic and proinflammatory effects of angiotensin II and aldosterone are very well demonstrated; however, their actions on antifibrotic factors expression are unknown. In order to explore this, we used RenTgKC mice overexpressing renin into the liver, leading to an increased plasma angiotensin II and thus induction of severe hypertension, and AS mice overexpressing aldosterone synthase (AS) in cardiomyocytes which have a doubled intracardiac aldosterone concentration. Male AS mice have a dysfunction of the coronary arteries relaxation without structural and functional changes of the myocardium. Mice derived from a crossing between the RenTgKC and AS strains were used in this work. It is shown that angiotensin II induces the expression of BNP and BMPs which ultimately slows the progression of myocardial fibrosis, and that aldosterone inhibits the expression of these factors and thus worsens the fibrosis.
    No preview · Article · May 2012 · Annales de cardiologie et d'angeiologie
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    ABSTRACT: The renin-angiotensin-aldosterone system is involved in the arterial hypertension-associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-β1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4).
    Preview · Article · Apr 2012 · Hypertension

Publication Stats

4k Citations
587.54 Total Impact Points

Institutions

  • 1999-2015
    • Paris Diderot University
      • Biologie Fonctionnelle et Adaptative (BFA) EA 4413
      Lutetia Parisorum, Île-de-France, France
  • 1983-2015
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1988-2010
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France