Key result
Endothelial cell-specific mineralocorticoid receptor deletion prevented Western diet-induced diastolic dysfunction and associated biochemical and structural abnormalities in male mice.
Why the study?
The mechanisms underlying diastolic dysfunction in obesity are poorly understood, and the specific role of endothelial cell-specific mineralocorticoid receptor activation in male mice has not been clarified.
Does endothelial cell-specific mineralocorticoid receptor deletion prevent Western diet-induced diastolic dysfunction in male mice?
Does endothelial cell-specific mineralocorticoid receptor deletion prevent Western diet-induced diastolic dysfunction in male mice?
Endothelial cell-specific mineralocorticoid receptor deletion prevents obesity-induced diastolic dysfunction in male mice, highlighting a potential therapeutic target for HFpEF.
Answers are grounded in this paper and cite their sources.
Endothelial MR may be a therapeutic target in diet-induced DD; hypothesis-generating in animals, requires human validation.
Widespread consumption of diets high in fat and fructose (Western diet, WD) has led to increased prevalence of obesity and diastolic dysfunction (DD). DD is a prominent feature of heart failure with preserved ejection fraction (HFpEF). However, the underlying mechanisms of DD are poorly understood, and treatment options are still limited. We have previously shown that deletion of the cell-specific mineralocorticoid receptor in endothelial cells (ECMR) abrogates DD induced by WD feeding in female mice. However, the specific role of ECMR activation in the pathogenesis of DD in male mice has not been clarified. Therefore, we fed 4-wk-old ECMR knockout (ECMRKO) male mice and littermates (LM) with either a WD or chow diet (CD) for 16 wk. WD feeding resulted in DD characterized by increased left ventricle (LV) filling pressure ( E/ e′) and diastolic stiffness [ E/ e′/LV inner diameter at end diastole (LVIDd)]. Compared with CD, WD in LM resulted in increased myocardial macrophage infiltration, oxidative stress, and increased myocardial phosphorylation of Akt, in concert with decreased phospholamban phosphorylation. WD also resulted in focal cardiomyocyte remodeling, characterized by areas of sarcomeric disorganization, loss of mitochondrial electron density, and mitochondrial fragmentation. Conversely, WD-induced DD and associated biochemical and structural abnormalities were prevented by ECMR deletion. In contrast with our previously reported observations in females, WD-fed male mice exhibited enhanced Akt signaling and a lower magnitude of cardiac injury. Collectively, our data support a critical role for ECMR in obesity-induced DD and suggest critical mechanistic differences in the genesis of DD between males and females.
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Aroor et al. (2022) studied Obesity-induced diastolic dysfunction. Endothelial cell-specific mineralocorticoid receptor (ECMR) deletion vs. Littermates (wild-type) was evaluated on Diastolic dysfunction (LV filling pressure and diastolic stiffness). Endothelial cell-specific mineralocorticoid receptor deletion prevented Western diet-induced diastolic dysfunction and associated biochemical and structural abnormalities in male mice.
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