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MIALET-PEREZ, Jeanne/0000-0002-1765-0283; O, Lairez/0000-0001-8141-6582; Sicard, Pierre/0000-0001-5837-3916; Vindis, Cecile/0000-0003-2421-1155; Schiltz, Odile/0000-0002-3606-2356; Santin, Yohan/0000-0002-9229-1161 WOS:000534930000012 PubMed: 31819159 Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2 as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa(2+) mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling.

Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n = 53) or high-fat, high-sucrose diet ( n = 66) for 6 mo. After 2 mo of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation. Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for an additional 8 wk or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry, and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 wk resulted in a higher working power developed by MI animals with diabetes and improved glycaemia but not ejection fraction or pathological phenotype. In contrast, exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet.NEW & NOTEWORTHY Exercise training is beneficial in patients with heart failure (HF) or diabetes. However, less is known of the possible benefit of exercise training for HF patients with diabetes. Using a rat model where both diabetes and MI had been induced, we showed that 2 mo after MI, 8 wk of exercise training failed to improve cardiac function and metabolism in diabetic animals in contrast to lean animals.

International audience; Aims: Recent studies reported that cAMP-binding protein Epac1-deficient mice were protected against various forms of cardiac stress, suggesting that pharmacological inhibition of Epac1 could be beneficial for the treatment of cardiac diseases. To test this assumption, we characterized an Epac1-selective inhibitory compound and investigated its potential cardioprotective properties.Methods and results: We used the Epac1-BRET (bioluminescence resonance energy transfer) for searching for non-cyclic nucleotide Epac1 modulators. A thieno[2,3-b]pyridine derivative, designated as AM-001 was identified as a non-competitive inhibitor of Epac1. AM-001 has no antagonist effect on Epac2 or protein kinase A activity. This small molecule prevents the activation of the Epac1 downstream effector Rap1 in cultured cells, in response to the Epac1 preferential agonist, 8-CPT-AM. In addition, we found that AM-001 inhibited Epac1-dependent deleterious effects such as cardiomyocyte hypertrophy and death. Importantly, AM-001-mediated inhibition of Epac1 reduces infarct size after mouse myocardial ischaemia/reperfusion injury. Finally, AM-001 attenuates cardiac hypertrophy, inflammation and fibrosis, and improves cardiac function during chronic β-adrenergic receptor activation with isoprenaline (ISO) in mice. At the molecular level, ISO increased Epac1-G protein-coupled receptor kinase 5 (GRK5) interaction and induced GRK5 nuclear import and histone deacetylase type 5 (HDAC5) nuclear export to promote the activity of the prohypertrophic transcription factor, myocyte enhancer factor 2 (MEF2). Inversely, AM-001 prevented the non-canonical action of GRK5 on HDAC5 cytoplasmic shuttle to down-regulate MEF2 transcriptional activity.Conclusion: Our study represents a ‘proof-of-concept’ for the therapeutic effectiveness of inhibiting Epac1 activity in cardiac disease using small-molecule pharmacotherapy.

Rationale: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood. Objective: To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury. Methods and Results: We show that Epac1 (exchange protein directly activated by cAMP 1) genetic ablation ( Epac1 −/− ) protects against experimental myocardial ischemia/reperfusion injury with reduced infarct size and cardiomyocyte apoptosis. As observed in vivo, Epac1 inhibition prevents hypoxia/reoxygenation–induced adult cardiomyocyte apoptosis. Interestingly, a deleted form of Epac1 in its mitochondrial-targeting sequence protects against hypoxia/reoxygenation–induced cell death. Mechanistically, Epac1 favors Ca 2+ exchange between the endoplasmic reticulum and the mitochondrion, by increasing interaction with a macromolecular complex composed of the VDAC1 (voltage-dependent anion channel 1), the GRP75 (chaperone glucose-regulated protein 75), and the IP3R1 (inositol-1,4,5-triphosphate receptor 1), leading to mitochondrial Ca 2+ overload and opening of the mitochondrial permeability transition pore. In addition, our findings demonstrate that MitEpac1 inhibits isocitrate dehydrogenase 2 via the mitochondrial recruitment of CaMKII (Ca 2+ /calmodulin-dependent protein kinase II), which decreases nicotinamide adenine dinucleotide phosphate hydrogen synthesis, thereby, reducing the antioxidant capabilities of the cardiomyocyte. Conclusions: Our results reveal the existence, within mitochondria, of different cAMP–Epac1 microdomains that control myocardial cell death. In addition, our findings suggest Epac1 as a promising target for the treatment of ischemia-induced myocardial damage.

Background: Concentrations of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in peripartum cardiomyopathy (PPCM). In this study we investigated changes in the angiogenesis balance in PPCM. Methods and Results: Plasma concentrations of sFlt-1 and the pro-angiogenic placenta growth factor (PlGF) were determined in patients with PPCM during the post-partum phase (n=83), in healthy women at delivery (n=30), and in patients with acute heart failure (AHF; n=65). Women with cardiac failure prepartum or associated with any form of hypertension, including pre-eclampsia, were excluded. Compared with non-pregnant women, in women with AHF and PPCM, median PlGF concentrations were greater (19 [IQR 16–22] and 98 [IQR 78–126] ng/mL, respectively; P0.94. Median plasma concentrations of the anti-angiogenic factor relaxin-2 were lower in PPCM and AHF (0.3 [IQR 0.3–1.7] and 0.3 [IQR 0.3–1] ng/mL, respectively) compared with normal deliveries (1,807 [IQR 1,101–4,050] ng/mL; P

Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell–specific conditional RBPJκ knockout. At baseline, both genotypes exhibited a cardiac arteriolar rarefaction associated with oxidative stress. In response to angiotensin II–induced hypertension, the heart of Notch3 knockout and SM- RBPJκ knockout mice did not adapt to pressure overload and developed heart failure, which could lead to an early and fatal acute decompensation of heart failure. This cardiac maladaptation was characterized by an absence of media hypertrophy of the media arteries, the transition of smooth muscle cells toward a synthetic phenotype, and an alteration of angiogenic pathways. A subset of mice exhibited an early fatal acute decompensated heart failure, in which the same alterations were observed, although in a more rapid timeframe. Altogether, these observations indicate that Notch3 plays a major role in coronary adaptation to pressure overload. These data also show that the hypertrophy of coronary arterial media on pressure overload is mandatory to initially maintain a normal cardiac function and is regulated by the Notch3/RBPJκ pathway.

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.

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).

Introduction Des donnees in vitro suggerent que l’inhibition pharmacologique des proteines EPAC, des regulateurs du signal cytoplasmique de l’AMPc, s’accompagne d’anomalies quantitatives et qualitatives de l’expression de l’aquaporine-2 (AQP2) dans les cellules principales du canal collecteur, en particulier lors d’une stimulation prolongee des recepteurs AVPR2 par l’ADH. EPAC1 ou EPAC2 pourraient etre de nouvelles cibles therapeutiques dans les pathologies impliquant la voie de signalisation ADH/AVPR2/AMPc/AQP2 (SIADH, diabete insipide, polykystose renale). Patients et methodes Dans des souris invalidees pour Epac1 (Epac1-/-) et des souris sauvages (wt), les parametres suivants ont ete mesures a l’etat basal, apres injection de ddAVP ou de furosemide, et apres restriction hydrique prolongee (RH30) : osmolarite, sodium, potassium, magnesium, calcium, uree, creatinine (sang et urine) ; histologie renale ; expression d’AQP2 (qPCR, WB et microscopie confocale) et d’Avpr2, Nkcc, Nkcc2, UT-1, Aqp1, Aqp8 (qPCR). Resultats A l’etat basal, l’osmolarite urinaire et serique des souris Epac1-/- et wt ne different pas, tout comme les concentrations d’electrolytes. L’expression des autres acteurs de l’homeostasie hydrique n’est pas modifiee. De meme, apres stimulation aigue (ddAVP) ou prolongee (RH30) du recepteur AVPR2, les capacites de reabsorption hydrique des souris Epac1-/- et wt sont identiques. La reponse au furosemide est egalement conservee (diurese, osmolarite). De fait, l’expression (ARNm et proteine) d’AQP2, tout comme son adressage a la membrane apicale chez les souris Epac1-/- sont identiques aux controles. En revanche, on note chez les souris wt une augmentation significative de l’expression d’EPAC1 sans modification d’EPAC2 apres RH30 (WB). Chez les souris Epac1-/-, l’expression d’EPAC2 est significativement diminuee apres RH30 (WB). Discussion Contrairement aux donnees in vitro utilisant un blocage pharmacologique visant EPAC1 et EPAC2, les souris Epac1-/- ne presentent pas de trouble franc de concentration des urines, suggerant une redondance des voies de signalisation et/ou une action combinee d’EPAC1 et EPAC2. Conclusion Chez la souris, l’invalidation isolee d’EPAC1 ne s’accompagne pas d’anomalie de l’expression d’AQP2 et de la reabsorption d’eau.

Background— Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. Methods and Results— Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin −/− ) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P P 2+ /calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras–GTPase–activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. Conclusions— Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca 2+ /calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure.

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.

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. Male 3-wk-old aldosterone synthase (AS)-overexpressing mice and their control wild-type (WT) littermates were fed a standard or high-fat, high-sucrose (HFHS) diet. After 6 mo of diet treatment, mice were euthanized, and cardiac samples were assayed by RT-PCR, immunoblotting, and immunohistology. HFHS diet induced type-2 diabetes in WT (WT-D) and AS (AS-D) mice. VEGFa mRNAs decreased in WT-D (-43%, P

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent 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.

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-s, 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.

5 Epac1 deletion prevents cardiomyocyte apoptosis during ischemia/reperfusion {#article-title-2} Introduction: Early coronary reperfusion has been established as the best therapeutic strategy to limit infarct size and improve prognosis. Therefore, elucidating the mechanisms underlying cardiomyocyte death may yield novel therapeutic targets to limit ischemia reperfusion (I/R) injury. I/R is accompanied and influenced by perturbations of the β-adrenergic receptor pathway which acts through cAMP dependent signaling cascade to modulate cardiac function and remodeling. Purpose: Although the involvement of the cAMP-binding protein Epac1 in cardiac hypertrophy and arrhythmia has been recently described, its role in I/R induced-cardiomyocyte death has not yet been investigated. Methods: Isolated adult cardiomyocytes from Epac1 knock-out (Epac1-/-) mice or wild-type (WT) littermates were exposed to hypoxia (HX) for 4h and 2h of reoxygenation period (HX+R). Cell death was determined by Trypan blue staining and LDH release. The mitochondrial permeability transition pore (mPTP) opening was monitored by the calcein loading CoCl(2)-quenching technique. The area at risk was examined by Evans blue and infarct size was evaluated by TTC staining. Results: Our data showed that HX+R-induced cardiomyocyte death were significantly prevented in adult cardiomyocytes isolated from Epac1-/- mice. In addition, we found that the increased expression of apoptotic markers (Bax, cleaved Caspase-9,Caspase-3) during HX+R conditions were also inhibited in Epac1-/- cardiomyocytes compared to WT cells. Interestingly, HX+R induced a decrease in calcein fluorescence corresponding to mPTP opening (56%±1.1 vs control cells set at 100%) in WT cardiomyocytes while genetic deletion of Epac1 prevented mPTP opening in HX+R conditions. Concomitantly, we found that the infarct size was significantly reduced in the Epac1-/- mice compared to the WT animals (53±4 % vs 33±4%, p

Background 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. Methodology/Principal Findings 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

Introduction Les pathologies cardiovasculaires liees a la grossesse sont associee a un risque majeur de morbi-mortalite. La prise en charge peri-obstetricale de la pre eclampsie a beneficie d’avancees recentes basees sur une meilleure maitrise de sa physiopathologie : desequilibre de la balance angiogenique mis en evidence par l’augmentation du ratio sFlt-1/PlGF dans le plasma maternel. La cardiomyopathie du peripartum (CMPP) est une forme d’insuffisance aigue grave, souvent pendant l’allaitement, qui peut se transformer en choc cardiogenique et necessiter la mise sous assistance ventriculaire et parfois la transplantation cardiaque. Malgre le pronostic grave de cette pathologie, aucun marqueur plasmatique ou urinaire n’est decrit a ce jour pour aider au diagnostic ou evaluer le pronostic. Il est a ce jour prouve sur des modeles animaux et confirme sur des series de patientes atteintes de CMPP que l’inhibition en post partum immediat de la secretion de prolactine (fraction 24 kD) par la bromocriptine, serait associee a un meilleur pronostic cardiaque. Nous emettons l’hypothese que la CMPP est associee a une alteration de la balance angiogenique et de celle de la relaxine-2, facteur placentatire aux proprietes hemodynamiques benefiques chez la femme enceinte. Materiel et methodes Les facteurs Anti (sFlt-1), pro (PlGF or VEGF) angiogeniques et la relaxine-2 ont ete mesures au niveau plasmatiques et tissulaires myocardiques chez des patientes (Afrique du Sud, France, Allemagne) ayant une CMPP. Les malades ont signe un accord ecrit. Resultats Les ratios sFlt-1/PlGF [1,3 (0,9 a 2,8)] et sFlt-1/VEGF [0,6 (0,2 a 1,2)] sont effondres chez les CMPP versus 52,8 (20,6 a 116,2) chez les femmes allaitantes ayant une fonction cardiaque normale. De plus les seuils plasmatiques de sFlt-1/PlGF Discussion Cette etude montre une alteration plasmatique et tissulaire myocardique de la balance angiogenique ainsi que de la secretion de la Relaxine-2, chez les patientes qui developpent une CMPP. L’association d’un bas ratio sFlt-1/PlGF et d’un taux bas de Relaxine-2 plasmatiques sont associes au diagnostic de CMPP. Ces resultats permettront de detecter dans un contexte de peri-partum les patientes atteintes de CMPP, pour instaurer rapidement un traitement par la bromocriptine. Des etudes complementaires pour une evaluation de l’effet de la serelaxine (Relaxine-2 recombinante humaine) seraient a prevoir au cours de la CMPP.

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

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

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 Conclusions To our knowledge, this is the first study providing new insights into the mechanisms whereby aldosterone prevents diabetes-induced cardiac disorders.

Introduction The pathogenesis of diabetic cardiomyopathy is not fully elucidated. Numerous factors may contribute to the development of heart failure in a diabetic context, including the scarcity of microvasculature and neurohumoral dysregulation, particularly the renin-angiotensin-aldosterone-system. We have previously shown that a modest increase of intracardiac aldosterone prevents the development of cardiomyopathy in mice with type 1 diabetes, possibly through a prevention of cardiac capillary dropout (Messaoudi et al, Faseb J 2009). This study aimed to determine the pathophysiological effects and to study transduction pathways of insulin in the case of a cardiac hyperaldosteronism with or without type 2 diabetes (T2D). Materiels et methodes 3 week-old mice overexpressing aldosterone synthase (AS), n = 9, and their wild-type (WT) littermates n = 5 were fed a high fat, high sucrose diet (HFHSD : 41 % fat, 43 % carbohydrate) or a standard diet ad libitum . After 4 months of diet, glucose and insulin tolerance tests were performed. Echocardiography was done, mice were sacrificed and tissue samples were used for RT-PCR, for immunoblotting and histological analyses. In addition, to analyze the signaling pathways dependent of the insulin receptor and insulin growth factor receptor, some of these mice (n = 5 for each group) received a dose of insulin (1 UI/kg body weight) 30 minutes before the sacrifice (Shimizu et al, JCI 2010). Resultats After 4 months of HFHSD, both WT-D and AS-D mice had hyperglycemia (+55 %, 56 %, P Conclusion The results indicate that in mice developing T2D the AKT signaling pathway in heart could be stimulated by insulin only when cardiac hyperaldosteronism was present. This aldosterone-dependent activation of the AKT pathway might play a role in the induction of VEGFa in heart.