Role of p38 mitogen-activated protein kinase in vascular endothelial aging: Interaction with Arginase-II and S6K1 signaling pathway

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 p38α 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.

Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

“…of inflammatory adhesion molecules, cytokines, and matrix metalloproteinases, collectively referred to as SASP325. To determine if our treatment with TNFα would also induce components of the SASP, we assessed the endothelial adhesion proteins ICAM-1 and E-selectin, the prothrombotic PAI-1, IGFBP-5, as well as two cytokines IL-6 and IL-8, shown previously to be elevated in endothelial cells at replicative senescence737383940. Levels of ICAM-1, E-selectin, IL-6, and IL-8 in TNFα-treated cells were determined using cell ELISA41 and levels of PAI-1 and IGFBP-5 mRNA were measured using qPCR.…”

“…In the present work, we chose to assess the expression of the adhesion molecules E-selectin and ICAM-1, as well as of PAI-1, IGFBP-5, IL-6, and IL-8, previously reported to be upregulated in senescence7373839405253. We found that the expression levels of all of these proteins were elevated after six days of treatment, and with the exception of PAI-1, remained high for at least three further days of cell culturing in normal growth medium, thereby supporting the notion of their senescence.…”

Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity

“…At this stage, the mechanisms of upregulation of Arg-II in kidney are not known. In the vascular cells, Arg-II upregulation involves activation of mTOR/S6K1 and p38mapk signaling pathways (Yepuri et al, 2012; Xiong et al, 2013, 2014; Wu et al, 2015). Whether these mechanisms are also involved in the obesity-associated renal injury remains to be investigated.…”

Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging

“…Recent research (13)(14)(15)(16)(17)(18)(19)(20)(21) has demonstrated an important role of arginase in age-associated vascular dysfunction, cellular senescence, apoptosis, and chronic inflammatory diseases such as atherosclerosis and obesity-associated insulin resistance. There are two arginase isoforms encoded by different genes (i.e., the cytoplasmic hepatic protein arginase-I) that mainly functions in the urea cycle for the detoxification of ammonia and the mitochondrial extrahepatic protein arginase-II (Arg-II) (22).…”