Abstract
p38 mitogen-activated protein kinase (p38) regulates cellular senescence and senescence-associated secretory phenotype (SASP), i.e., secretion of cytokines and/or chemokines. Previous work showed that augmented arginase-II (Arg-II) and S6K1 interact with each other to promote endothelial senescence through uncoupling of endothelial nitric oxide synthase (eNOS). Here we demonstrate eNOS-uncoupling, augmented expression/secretion of IL-6 and IL-8, elevation of p38 activation and Arg-II levels in senescent endothelial cells. Silencing Arg-II or p38α in senescent cells recouples eNOS and inhibits IL-6 and IL-8 secretion. Overexpression of Arg-II in young endothelial cells causes eNOS-uncoupling and enhances IL-6 and IL-8 expression/secretion, which is prevented by p38 inhibition or by antioxidant. Moreover, p38 activation and expression of IL-6 and KC (the murine IL-8 homologue) are increased in the heart and/or aortas of wild type (WT) old mice, which is abolished in mice with Arg-II gene deficiency (Arg-II-/-). In addition, inhibition of p38 in the old WT mice recouples eNOS function and reduces IL-6 and KC expression in the aortas and heart. Silencing Arg-II or p38a or S6K1 inhibits each other in senescence endothelial cells. Thus, Arg-II, p38, and S6K1 form a positive circuit which regulates endothelial senescence and cardiovascular aging.
Highlights
Aging is a major risk factor for cardiovascular disease and is associated with increased oxidative stress and accumulation of senescent endothelial cells in the vasculature [1,2,3]
Aging-associated endothelial dysfunction, functional defect of endothelial nitric oxide synthase (eNOS) such as eNOS-uncoupling rather than decreased eNOS gene expression is considered as one of the most important mechanisms linking to age-associated cardiovascular diseases [3, 34]. eNOS-uncoupling associates with advanced aging or cellular senescence, and plays a causative role in promoting vascular aging and endothelial cell senescence [4, 35, 36], which is involved in acceleration of vascular diseases including atherosclerosis and diabetic vascular complications [37, 38]
Cell senescence is viewed as a stress response to diverse stimuli, which is manifested by active release of inflammatory cytokines such as IL-6 and IL-8, etc., i.e., senescence-associated secretary phenotypes (SASP), leading to functional alterations of the cells through autocrine or paracrine mechanisms [39]
Summary
Aging is a major risk factor for cardiovascular disease and is associated with increased oxidative stress and accumulation of senescent endothelial cells in the vasculature [1,2,3]. Studies demonstrate that senescent endothelial cells accumulate in the blood vessels with age [6, 7] and in atherosclerosis [8, 9], which may importantly contribute to age-accelerated atherogenesis. P38 is activated by dual phosphorylation mediated by the upstream kinases, i.e., MAPK kinases, MKK3 and MKK6 [13] and has been shown to play an essential role in cell senescence and SASP [14, 15].
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