Mechanical stretch inhibits oxidized low density lipoprotein-induced apoptosis in vascular smooth muscle cells by up-regulating integrin alphavbeta3 and stablization of PINCH-1.
To determine the mechanisms involved in regulating the balance between apoptosis and survival in vascular smooth muscle cells (VSMC), we studied anti-apoptotic stimuli that can counteract pro-apoptotic events in the process of early atherosclerotic lesions formation. Such a process involves VSMC accumulation even in the presence of oxidized low density lipoprotein (Ox-LDL). In the arch of the aorta, we find that integrin beta3 is higher than in descending arteries. In the advanced atherosclerosis lesion, we found an inverse correlation between the level of integrin beta3 and apoptosis (deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive). We also found an increase in integrin alphaVbeta3 (but not integrin beta1) expression in VSMC that are subjected to cyclic stretch. VSMC subjected to stretch as well as VSMC with forced expression of alphaVbeta3 were demonstrated to be resistant to Ox-LDL-induced cytoskeleton disruption and apoptosis. The anti-apoptotic effect of stretch was abolished by treatment of VSMC with small interfering RNA against integrin beta3 as well as VSMC isolated from integrin beta3 knock-out mice. Disruption of the cytoskeleton abolished the protective effect of stretch or alphaVbeta3 overexpression on Ox-LDL-induced activation of Bax and apoptosis. We also demonstrated that stretch-mediated protection of Ox-LDL-induced apoptosis involved stabilization of PINCH-1; Ox-LDL decreased the level of PINCH-1, but the application of mechanical stretch or overexpression of either integrin beta1 or integrin beta3 prevented its down-regulation. In the arteries of integrin beta3 null mice, there were lower levels of PINCH-1 and ILK-1. Moreover, deletion of integrin beta3 in VSMC abolished the stretch protective effect on PINCH-1. Small interfering RNA-mediated knockdown of PINCH-1 disrupted the cytoskeleton and caused apoptosis of VSMC. These findings provided experimental evidence that mechanical stretch acted as a survival factor in the arches of aortas. Furthermore, mechanical stretch prevented VSMC from apoptosis via a mechanism that involves alphaVbeta3 integrin expression, stabilization of PINCH-1, and remodeling of the cytoskeleton.
Cheng
Jizhong
J
Department of Internal Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Zhang
Jiqiang
J
Merched
Aksam
A
Zhang
Liping
L
Zhang
Ping
P
Truong
Luan
L
Boriek
Aladin M
AM
Du
Jie
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis*; D019012:Integrin beta1 / Q000096:biosynthesis; D039661:Integrin beta3 / Q000378:metabolism; D060588:LIM Domain Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013314:Stress, Mechanical; D015854:Up-Regulation / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C494827:Bax protein, mouse; D004268:DNA-Binding Proteins; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D039661:Integrin beta3; D060588:LIM Domain Proteins; C490232:Lims1 protein, mouse; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; C099252:oxidized low density lipoprotein