内分泌学
内科学
磷化氢
盐皮质激素受体
舒张期
蛋白激酶B
心室
心力衰竭
生物
肌肉肥大
射血分数保留的心力衰竭
磷酸化
氧化应激
医学
醛固酮
血压
细胞生物学
作者
Annayya R. Aroor,Vincent G. DeMarco,Adam Whaley‐Connell,Guanghong Jia,Yan Yang,Neekun Sharma,Huma Naz,Chetan P. Hans,Melvin R. Hayden,Michael A. Hill,James R. Sowers,Camila Manrique‐Acevedo,Guido Lastra
出处
期刊:American Journal of Physiology-regulatory Integrative and Comparative Physiology
[American Physiological Society]
日期:2023-01-01
卷期号:324 (1): R90-R101
标识
DOI:10.1152/ajpregu.00274.2021
摘要
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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