Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-11, Vol.108 (18), p.2264-2269
• Main Authors: MINAMINO, Tohru, YOSHIDA, Toshihiko, TATENO, Kaoru, MIYAUCHI, Hideyuki, YONZENG ZOU, TOKO, Haruhiro, KOMURO, Issei
• Format: Article
• Language: English
• Subjects: Adult; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Cellular Senescence - drug effects; Cellular Senescence - physiology; Cytokines - biosynthesis; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Activation; Gene Transfer Techniques; Humans; Inflammation - drug therapy; Inflammation - pathology; Medical sciences; Mitogen-Activated Protein Kinases - metabolism; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; ras Proteins - genetics; ras Proteins - pharmacology; ras Proteins - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000093274.82929.22

Vascular cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related vascular disorders. Ras, an important signaling molecule involved in atherogenic stimuli, is known to promote aging in yeast and cellular senescence in primary human fibroblasts. The aim of this study was to investigate the role of Ras-induced vascular smooth muscle cell (VSMC) senescence in atherogenesis. We introduced an activated ras allele (H-rasV12) into human VSMCs using retroviral infection. Introduction of H-rasV12 induced a growth arrest with phenotypic characteristics of cellular senescence, such as enlarged cell shapes and increases in expression of cyclin-dependent kinase inhibitors and senescence-associated beta-galactosidase (SA-beta-gal) activity. Activation of Ras drastically increased expression of proinflammatory cytokines, in part through extracellular signal-regulated kinase activation. To determine whether Ras activation induces cellular senescence in vivo, we transduced the adenoviral vector encoding H-rasV12 into rat carotid arteries injured by a balloon catheter. Introduction of Ras into the arteries enhanced vascular inflammation and senescence compared with mock-infected injured arteries. Moreover, SA-beta-gal-positive VSMCs were detected in the intima of advanced human atherosclerotic lesions and exhibited increased levels of extracellular signal-regulated kinase activity and proinflammatory cytokine expression. Our results suggest that atherogenic stimuli mediated by Ras induce VSMC senescence and vascular inflammation, thereby contributing to atherogenesis. This novel mechanism of atherogenesis may provide insights into a new antisenescence treatment for atherosclerosis.