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J. Biol. Chem., Vol. 282, Issue 47, 34268-34275, November 23, 2007

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Mechanical Stretch Inhibits Oxidized Low Density Lipoprotein-induced Apoptosis in Vascular Smooth Muscle Cells by Up-regulating Integrin V3 and Stablization of PINCH-1^*

From the Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 77030

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 3 is higher than in descending arteries. In the advanced atherosclerosis lesion, we found an inverse correlation between the level of integrin 3 and apoptosis (deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive). We also found an increase in integrin V3 (but not integrin 1) expression in VSMC that are subjected to cyclic stretch. VSMC subjected to stretch as well as VSMC with forced expression of V3 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 3 as well as VSMC isolated from integrin 3 knock-out mice. Disruption of the cytoskeleton abolished the protective effect of stretch or V3 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 1 or integrin 3 prevented its down-regulation. In the arteries of integrin 3 null mice, there were lower levels of PINCH-1 and ILK-1. Moreover, deletion of integrin 3 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 V3 integrin expression, stabilization of PINCH-1, and remodeling of the cytoskeleton.

Received for publication, April 12, 2007 , and in revised form, September 17, 2007.

^* This work was supported by National Institute of Health Grants RO1 HL 70762, HL63134, and P50-DK064233. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Baylor College of Medicine, Division of Nephrology, One Baylor Plaza, BCM N-520 Houston, TX 77030. Tel.: 713-798-1301; Fax: 713-798-5010; E-mail: jdu{at}bcm.edu.

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