期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 6, 期 10, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.117.006421
关键词
aging; stress; vascular biology; vascular disease; vascular endothelium
资金
- National Natural Science Foundation of China [81560240, 81560149, 81460082]
- Ministry of Education, Culture, Sports, Science and Technology of Japan Society for the Promotion of Science (JAPAN) [15H04801, 15H04802]
- Novartis Aging
- Japan Geriatrics Society (JAPAN) [27-007756]
- Grants-in-Aid for Scientific Research [15H04802, 15H04801] Funding Source: KAKEN
Background-Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin-mediated peroxisome proliferator activated receptor-gamma/its co-activator 1 alpha (PGC-1 alpha) activation. Methods and Results-Seven-week-old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP-1 and adiponectin in plasma and phospho-AMP-activated protein kinase alpha(p-AMPK alpha), vascular endothelial growth factor, peroxisome proliferator activated receptor-gamma, PGC-1 alpha, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31(+)/c-Kit(+) progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP-1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion. Conclusions-These results indicate that the DPP4/GLP-1-adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions.
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