Cardiomyocyte-specific overexpression of oestrogen receptor β improves survival and cardiac function after myocardial infarction in female and male mice

Abstract ERβ (oestrogen receptor β) activation has been shown to be cardioprotective, but the cell types and mechanisms involved are not understood. To investigate whether ERβ restricted to cardiomyocytes contributes to the observed cardioprotection, we tested the effects of cardiomyocyte-specific ERβ-OE (ERβ overexpression) on survival, cardiac remodelling and function after MI (myocardial infarction) and studied the molecular pathways potentially involved. Female and male mice with cardiomyocyte-specific ERβ-OE and WT (wild-type) littermates were subjected to chronic anterior coronary artery ligation or sham surgery. Two weeks after MI, ERβ-OE mice showed improved survival (100 % and 83 % compared with 76 % and 58 % in WT females and males respectively). ERβ-OE was associated with attenuated LV (left ventricular) dilatation, smaller increase in heart weight, less lung congestion at similar MI size, and improved systolic and diastolic function in both sexes. We identified two potential pathways for ERβ-mediated myocardial protection. First, male and female ERβ-OE mice had a lower reduction of SERCA2a (sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a) expression after MI, suggesting less reduction in diastolic Ca 2+ -reuptake into the sarcoplasmic reticulum post-MI. Secondly, male ERβ-OE revealed attenuated cardiac fibrosis in the remote LV tissue and expression of fibrosis markers collagen I and III, periostin and miR-21. Cardiomyocyte-specific ERβ-OE improved survival associated with reduced maladaptive remodelling, improved cardiac function and less heart failure development after MI in both sexes. These effects seem to be related, at least in part, to a better maintenance of Ca 2+ cycling in both sexes and a lower induction of cardiac fibrosis in males after MI

Cardiomyocyte-specific overexpression of estrogen receptor beta improves survival and cardiac function after myocardial infarction in female and male mice

Abstract Background: Estrogen receptor beta (ER ) activation has been shown to be cardioprotective, but the involved cell types and mechanisms are not understood. To investigate whether ER restricted to cardiomyocytes contributes to observed cardioprotection, we tested the effects of a cardiomyocyte-specific ER overexpression (ER -OE) on survival, cardiac remodelling and function after myocardial infarction (MI) and studied potentially involved molecular pathways. Methods and Results: Female and male mice with cardiomyocyte-specific ER -OE and wild type (WT) littermates were subjected to chronic anterior coronary artery ligation or sham surgery. Two weeks after MI, ER -OE mice showed improved survival (100 and 83% vs 76 and 58% in WT females and males respectively). ER -OE was associated with attenuated left ventricular (LV) dilatation, smaller increase in heart weight, less lung congestion at similar MI size, and improved systolic and diastolic function in both sexes. We identified two potential pathways for ER mediated myocardial protection. First, male and female ER -OE mice had a lower reduction of SERCA2a expression after MI, suggesting less reduction in diastolic Ca 2+ -reuptake into sarcoplasmic reticulum post MI. Second, male ER -OE revealed attenuated cardiac fibrosis in the remote LV tissue and expression of fibrosis markers Col I, Col III, periostin, and miR21. Conclusions: Cardiomyocyte-specific ER -OE improved survival associated with reduced maladaptive remodelling, improved cardiac function and less heart failure development after MI in both sexes. These effects seem to be related, at least in part, to a better maintenance of Ca 2+ -cycling in both sexes and a lower induction of cardiac fibrosis in males after MI. Summary statement: The study provides new insights into cardiomyocyte-specific effects of ER in the setting of chronic MI using a transgenic mouse model. ER -OE mice of both sexes showed improved survival, less maladaptive LV remodelling, better cardiac function and less HF development. Short title: Effects of ER overexpression after M

Endothelial Gata5 transcription factor regulates blood pressure

Despite its high prevalence and economic burden, the aetiology of human hypertension remains incompletely understood. Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP). GATA5 is expressed in microvascular endothelial cells and its genetic inactivation in mice (Gata5-null) leads to vascular endothelial dysfunction and hypertension. Endothelial-specific inactivation of Gata5 mimics the hypertensive phenotype of the Gata5-null mice, suggestive of an important role for GATA5 in endothelial homeostasis. Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways. Consistent with a role in human hypertension, we report genetic association of variants at the GATA5 locus with hypertension traits in two large independent cohorts. Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension

The Epidermal Growth Factor Receptor Is Involved in Angiotensin II But Not Aldosterone/Salt-Induced Cardiac Remodelling

Experimental and clinical studies have shown that aldosterone/mineralocorticoid receptor (MR) activation has deleterious effects in the cardiovascular system; however, the signalling pathways involved in the pathophysiological effects of aldosterone/MR in vivo are not fully understood. Several in vitro studies suggest that Epidermal Growth Factor Receptor (EGFR) plays a role in the cardiovascular effects of aldosterone. This hypothesis remains to be demonstrated in vivo. To investigate this question, we analyzed the molecular and functional consequences of aldosterone exposure in a transgenic mouse model with constitutive cardiomyocyte-specific overexpression of a mutant EGFR acting as a dominant negative protein (DN-EGFR). As previously reported, Angiotensin II-mediated cardiac remodelling was prevented in DN-EGFR mice. However, when chronic MR activation was induced by aldosterone-salt-uninephrectomy, cardiac hypertrophy was similar between control littermates and DN-EGFR. In the same way, mRNA expression of markers of cardiac remodelling such as ANF, BNF or β-Myosin Heavy Chain as well as Collagen 1a and 3a was similarly induced in DN-EGFR mice and their CT littermates. Our findings confirm the role of EGFR in AngII mediated cardiac hypertrophy, and highlight that EGFR is not involved in vivo in the damaging effects of aldosterone on cardiac function and remodelling

Mise en évidence d'un effet bénéfique de l'aldostérone sur la cardiomyopathie diabétique chez la souris (préservation de l'expression myocardique du VEGFa, de la densité capillaire et de la fonction cardiaque)

Ce travail visait à vérifier l'hypothèse que l'association d'une augmentation cardiaque d'aldostérone et d'un diabète est délétère. Pour ce faire, nous avons induit un diabète de type 1 (D) chez des souris wild-type (Wt) et chez des souris surexprimant l aldostérone synthase dans le cœur (Tg). Après 2 mois de diabète, l altération de la fonction ventriculaire des souris WT-D est accompagnée par une diminution de la densité capillaire et de l expression du VEGFa, tandis que la production d anion superoxyde et la carbonylation des protéines sont augmentées. Mise à part une légère augmentation de la carbonylation des protéines, toutes ces altérations sont indétectables chez les souris Tg-D. Le phénotype des Tg-D est réversible par l eplérénone (antagoniste de l aldosterone). En préservant l expression du VEGFa, l aldostérone contrecarre une série d événements physio-pathologiques perturbant l homéostasie microvasculaire dans le myocarde diabétique. Ces résultats supportent le concept d une étroite relation entre l expression du VEGFa, la microcirculation et la fonction contractile, indépendamment des conditions environnementales.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Well-Posedness and Numerical Study for Solutions of a Parabolic Equation with Variable-Exponent Nonlinearities

We consider the following nonlinear parabolic equation: ut-div(|∇u|p(x)-2∇u)=f(x,t), where f:Ω×(0,T)→R and the exponent of nonlinearity p(·) are given functions. By using a nonlinear operator theory, we prove the existence and uniqueness of weak solutions under suitable assumptions. We also give a two-dimensional numerical example to illustrate the decay of solutions

Cardiomyocyte-specific overexpression of oestrogen receptor improves survival and cardiac function after myocardial infarction in female and male mice

International audienceERβ (oestrogen receptor β) activation has been shown to be cardioprotective, but the cell types and mechanisms involved are not understood. To investigate whether ERβ restricted to cardiomyocytes contributes to the observed cardioprotection, we tested the effects of cardiomyocyte-specific ERβ-OE (ERβ overexpression) on survival, cardiac remodelling and function after MI (myocardial infarction) and studied the molecular pathways potentially involved. Female and male mice with cardiomyocyte-specific ERβ-OE and WT (wild-type) littermates were subjected to chronic anterior coronary artery ligation or sham surgery. Two weeks after MI, ERβ-OE mice showed improved survival (100% and 83% compared with 76% and 58% in WT females and males respectively). ERβ-OE was associated with attenuated LV (left ventricular) dilatation, smaller increase in heart weight, less lung congestion at similar MI size, and improved systolic and diastolic function in both sexes. We identified two potential pathways for ERβ-mediated myocardial protection. First, male and female ERβ-OE mice had a lower reduction of SERCA2a (sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2a) expression after MI, suggesting less reduction in diastolic Ca(2+)-reuptake into the sarcoplasmic reticulum post-MI. Secondly, male ERβ-OE revealed attenuated cardiac fibrosis in the remote LV tissue and expression of fibrosis markers collagen I and III, periostin and miR-21. Cardiomyocyte-specific ERβ-OE improved survival associated with reduced maladaptive remodelling, improved cardiac function and less heart failure development after MI in both sexes. These effects seem to be related, at least in part, to a better maintenance of Ca(2+) cycling in both sexes and a lower induction of cardiac fibrosis in males after MI

The Diuretic Torasemide Does Not Prevent Aldosterone-Mediated Mineralocorticoid Receptor Activation in Cardiomyocytes

International audienceAldosterone binds to the mineralocorticoid receptor (MR) and exerts pleiotropic effects beyond enhancing renal sodium reabsorption. Excessive mineralocorticoid signaling is deleterious during the evolution of cardiac failure, as evidenced by the benefits provided by adding MR antagonists (MRA) to standard care in humans. In animal models of cardiovascular diseases, MRA reduce cardiac fibrosis. Interestingly diuretics such as torasemide also appear efficient to improve cardiovascular morbidity and mortality, through several mechanisms. Among them, it has been suggested that torasemide could block aldosterone binding to the MR. To evaluate whether torasemide acts as a MRA in cardiomyocytes, we compared its effects with a classic MRA such as spironolactone. We monitored ligand-induced nuclear translocation of MR-GFP and MR transactivation activity in the cardiac-like cell line H9C2 using a reporter gene assay and known endogenous aldosterone-regulated cardiac genes. Torasemide did not modify MR nuclear translocation. Aldosterone-induced MR transactivation activity was reduced by the MRA spironolactone, not by torasemide. Spironolactone blocked the induction by aldosterone of endogenous MR-responsive genes (Sgk-1, PAI-1, Orosomucoid-1, Rgs-2, Serpina-3, Tenascin-X), while torasemide was ineffective. These results show that torasemide is not an MR antagonist; its association with MRA in heart failure may however be beneficial, through actions on complementary pathways

Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice

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