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Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling.

ABSTRACT: The peroxisome proliferator activated receptor-gamma (PPARgamma) protein is a nuclear transcriptional activator with importance in diabetes management as the molecular target for the thiazolidinedione (TZD) family of drugs. Substantial evidence indicates that the TZD family of PPARgamma agonists may retard the development of atherosclerosis. However, recent clinical data have suggested that at least one TZD may increase the risk of myocardial infarction and death from cardiovascular disease. In this study, we used a genetic approach to disrupt PPARgamma signaling to probe the protein's role in smooth muscle cell (SMC) responses that are important for atherosclerosis.SMC isolated from transgenic mice harboring the dominate-negative P465L mutation in PPARgamma (PPARgamma(L/+)) exhibited greater proliferation and migration then did wild-type cells. Upregulation of ETS-1, but not ERK activation, correlated with enhanced proliferative and migratory responses PPARgamma(L/+) SMCs. After arterial injury, PPARgamma(L/+) mice had a approximately 4.3-fold increase in the development of intimal hyperplasia.These findings are consistent with a normal role for PPARgamma in inhibiting SMC migration and proliferation in the context of restenosis or atherosclerosis.

SUBMITTER: Meredith D

PROVIDER: S-EPMC2773202 | biostudies-other | 2009 Apr

REPOSITORIES: biostudies-other

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Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling.

Meredith Dane D Panchatcharam Manikandan M Miriyala Sumitra S Tsai Yau-Sheng YS Morris Andrew J AJ Maeda Nobuyo N Stouffer George A GA Smyth Susan S SS

Arteriosclerosis, thrombosis, and vascular biology 20090129 4

<h4>Objective</h4>The peroxisome proliferator activated receptor-gamma (PPARgamma) protein is a nuclear transcriptional activator with importance in diabetes management as the molecular target for the thiazolidinedione (TZD) family of drugs. Substantial evidence indicates that the TZD family of PPARgamma agonists may retard the development of atherosclerosis. However, recent clinical data have suggested that at least one TZD may increase the risk of myocardial infarction and death from cardiovas ...[more]

PMID: 19179641

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Project description:Objective- Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results- We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress-induced intima thickening models, we compared neointimal hyperplasia in Apoe-/-, Cd36-/- /Apoe-/-, and CD36 specifically deleted in VSMC (VSMC cd36-/-) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36-/- /Apoe-/- compared with Apoe-/- mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36-/- mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36-/- VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36-/- VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36-/- VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-?1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle ? actin, and dramatically increased cell contraction. Conclusions- CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.

Dataset Information

Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling.

Publications

Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling.

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