Ablation of Mineralocorticoid Receptors in Myocytes But Not in Fibroblasts Preserves Cardiac Function

Abstract

Abstract-Antagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partially known. The aim of this work was to evaluate whether genetic deletion of mineralocorticoid receptors in mouse cardiomyocytes or fibroblasts in vivo is cardioprotective after chronic left ventricular pressure overload. After transverse aortic constriction, mice deficient in myocyte mineralocorticoid receptors but not those deficient in fibroblast mineralocorticoid receptors were protected from left ventricular dilatation and dysfunction. After pressure overload, left ventricular ejection fraction was significantly higher in mice lacking myocyte mineralocorticoid receptors (70.2Ϯ4.4%) as compared with control mice (54.3Ϯ2.5%; PϽ0.01). Myocyte mineralocorticoid receptor-deficient mice showed mild cardiac hypertrophy at baseline, contributing to reduced left ventricular wall tension at baseline and after pressure overload. Cardiac levels of phospho-extracellular signal-regulated kinase 1/2 were higher in myocyte mineralocorticoid receptor-deficient mice than in control mice after pressure overload. Neither fibroblast nor myocyte mineralocorticoid receptor ablation altered the development of cardiac hypertrophy or fibrosis after pressure overload. Both mineralocorticoid receptor mutant mouse strains developed similar degrees of myocyte apoptosis, proinflammatory gene expression, and macrophage infiltration after pressure overload. Thus, mineralocorticoid receptors in cardiac myocytes but not in fibroblasts protect from cardiac dilatation and failure after chronic pressure overload.

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

“…This was in contrast to selective MR deletion in cardiac fibroblasts, which did not have any beneficial effect (Lother et al. 2011). Our new data indicate that deletion of EC‐MR does not affect systolic function during homeostasis, but contributes to the development of systolic dysfunction in response to TAC without modulating cardiac hypertrophy, fibrosis, or diastolic function.…”

“…Studies using the TAC model, which reproduces this progression of cardiac remodeling leading to failure, demonstrated that specific deletion of MR from cardiac myocytes, but not cardiac fibroblasts, preserved systolic function despite no changes in pathological cardiac hypertrophy and fibrosis in response to left ventricular (LV) pressure overload (Lother et al. 2011). Studies using the hypertension model induced with the mouse mineralocorticoid deoxycorticosterone (DOCA) and salt, reported that myeloid cell‐specific MR knockout mice and mice with conditional deletion of MR in both myeloid cells and endothelial cells (EC), were protected from cardiac fibrosis, with the latter model also showing signs of decreased cardiac inflammation (Rickard et al.…”

Oxidative Stress Causes Mineralocorticoid Receptor Activation in Rat Cardiomyocytes

“…[2][3][4] Conversely, cardiomyocyte-specific MR knockout mice were protected against cardiac remodeling and contractile dysfunction after myocardial infarction 5 and chronic pressure overload. 6 The significance of MR activation in heart failure and hypertensive heart disease was highlighted by large-scale randomized clinical trials. 7,8 Although aldosterone excess is an important stimulus to MR, it was revealed that MR can also be activated in normal or even low-aldosterone states.…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

“…At later time points, cardiac function was significantly improved and the non-infarcted tissue showed less remodelling overall demonstrating a clear role for MR signalling in the detrimental remodelling in the post-infarct heart. In contrast, Lother and coworkers, using the same Cre recombinase and approach to generate MR null mice, investigated a model of pressure overload (TAC) and found that loss of cardiomyocyte MR did not change the tissue hypertrophy or fibrotic response, but left ventricular function was significantly improved (Lother et al 2011).…”