Abstract
Chronological aging is linked to cellular senescence, and there is accumulating evidence for a pathological role of cellular senescence in age-related disorders such as obesity, diabetes, and heart failure. The protein p53 has a central role in cellular senescence, and p53 expression in cardiomyocytes, vascular endothelial cells, adipocytes, and immune cells leads to the development of heart failure and diabetes. It is widely accepted that formation of capillary networks is critical for morphogenesis of organs and maintenance of homeostasis. Capillary rarefaction and hypoxia promote pathological changes in the myocardium of the failing heart, causing systolic dysfunction. Capillary rarefaction and hypoxia also cause dysfunction of brown adipose tissue (BAT), leading to systemic metabolic disorders with promotion of diabetes. Vascular endothelial cell senescence develops in heart failure and diabetes and is responsible for progression of these age-related disorders. In a murine model of left ventricular pressure overload, increased expression of p53 in vascular endothelial cells and bone marrow cells promotes inflammatory cell infiltration into the heart, contributing to cardiac remodeling and systolic dysfunction. Metabolic stress up-regulates p53 expression in endothelial cells, while reducing the phosphorylation of endothelial nitric oxide synthase (eNOS) and glucose transporter (GLUT)1 expression in these cells. These changes lead to suppression of mitochondrial biogenesis and glucose uptake in the skeletal muscle and promote the development of systemic metabolic dysfunction. Suppression of vascular aging and vascular dysfunction is critically important for maintenance of organ homeostasis and is essential for prevention or treatment of heart failure, obesity, and diabetes.
Highlights
Chronological aging increases the risk of age-related disorders such as obesity, diabetes, and heart failure
Studies have shown that endothelial cell senescence leads to cardiac inflammation, capillary rarefaction, and hypoxia, thereby promoting pathologic cardiac remodeling in response to left ventricular (LV) pressure overload [25, 42]
Accumulation of lipids leads to the suppression of vascular endothelial growth factor (VEGF)-A, a critical regulator of angiogenesis, and induces capillary rarefaction and hypoxia, promoting the whitening of brown fat and systemic metabolic dysfunction
Summary
Chronological aging increases the risk of age-related disorders such as obesity, diabetes, and heart failure. Capillary rarefaction and hypoxia cause dysfunction of brown adipose tissue (BAT) and promote systemic metabolic abnormalities [28]. In a murine model of left ventricular pressure overload, increased adrenergic signaling associated with heart failure was found to up-regulate p53 expression in both endothelial cells and bone marrow cells, contributing to cardiac inflammation and remodeling [42].
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