SM22α (Smooth Muscle Protein 22-α) Promoter-Driven IGF1R (Insulin-Like Growth Factor 1 Receptor) Deficiency Promotes Atherosclerosis
Year: 2018
Type: article
Abstract: Objective— IGF-1 (insulin-like growth factor 1) is a major autocrine/paracrine growth factor, which promotes cell proliferation, migration, and survival. We have shown previously that IGF-1 reduced atherosclerosis and promoted features of stable atherosclerotic plaque in Apoe −/ − mice—an animal model of atherosclerosis. The aim of this study was to assess effects of smooth muscle cell (SMC) IGF-1 signaling on the atherosclerotic plaque. Approach and Results— We generated Apoe −/− mice with IGF1R (IGF-1 receptor) deficiency in SMC and fibroblasts (SM22α [smooth muscle protein 22 α]-CreKI/IGF1R-flox mice). IGF1R was decreased in the aorta and adventitia of SM22α-CreKI/IGF1R-flox mice and also in aortic SMC, embryonic, skin, and lung fibroblasts isolated from SM22α-CreKI/IGF1R-flox mice. IGF1R deficiency downregulated collagen mRNA-binding protein LARP6 (La ribonucleoprotein domain family, member 6) and vascular collagen, and mice exhibited growth retardation. The high-fat diet–fed SM22α-CreKI/IGF1R-flox mice had increased atherosclerotic burden and inflammatory responses. α-SMA (α-smooth muscle actin)–positive plaque cells had reduced proliferation and elevated apoptosis. SMC/fibroblast-targeted decline in IGF-1 signaling decreased atherosclerotic plaque SMC, markedly depleted collagen, reduced plaque fibrous cap, and increased plaque necrotic cores. Aortic SMC isolated from SM22α-CreKI/IGF1R-flox mice had decreased cell proliferation, migration, increased sensitivity to apoptosis, and these effects were associated with disruption of IGF-1–induced Akt signaling. Conclusions— IGF-1 signaling in SMC and in fibroblast is a critical determinant of normal vascular wall development and atheroprotection.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: American Diabetes Association, U.S. Department of Veterans Affairs, American Heart Association, University of Missouri, Tulane University, National Institutes of Health, Medical School, University of Michigan, Japan Society for the Promotion of Science, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences
Awards: G1322863704, Regulatory mechanism of ubiquitin modification of insulin receptor substrates and its physiological and pathological significance., G193469588, G2377109628, G2575151841, 12/15-LIPOXYGENASE, INSULIN-LIKE GROWTH FACTOR-1 AND ATHEROSCLEROSIS, G4275872716, G6375788604, G6928093150, ANGIOTENSIN II, IGF-1 AND SKELETAL MUSCLE ATROPHY, G733420108, Development of methods to regulate abnormality of insulin-like activity by modulation of function of insulin receptor substrates-associated complex, Insulin-Like Growth Factor-1 and Atherosclerosis, Louisiana Clinical and Translational Science Center
OpenAlex ID: W2889533658