Pioglitazone Enhances Cytokine-Induced Apoptosis in Vascular Smooth Muscle Cells and Reduces Intimal Hyperplasia

Abstract

Background-Cytokines induce apoptosis in vascular disease lesions through enhancement of inducible nitric oxide (NO) synthase (iNOS) activation. The thiazolidinediones, novel insulin-sensitizing agents, have been demonstrated to modulate cytokine-induced NO production. We have investigated the role of pioglitazone in the apoptosis of vascular smooth muscle cells (VSMCs) in vitro and developed intimal hyperplasia in vivo. Methods and Results-Pioglitazone (0.1 to 10 mol/L) significantly enhanced cytokine-induced expression of iNOS and NO production in a dose-dependent manner in rat VSMCs, but 15-deoxy-⌬ 12,14 -prostaglandin J2 (up to 10 mol/L), a native peroxisome proliferator-activated receptor-␥ ligand, showed no effect. Pioglitazone also significantly enhanced reduction of cell viability, as evidenced by the increase in the number of TUNEL-positive cells. All of these effects of pioglitazone were blocked by treatment with N-monomethyl-L-arginine, an NO synthesis inhibitor. In an in vivo study with a balloon-injured rat carotid artery, neointimal thickness had reached maximum levels at 2 weeks after injury. Then, rats were fed with or without pioglitazone (3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) for an additional week. The ratio of intima to media area of carotid artery was significantly decreased by 30%, and the ratio of apoptotic cells in neointima was significantly increased in pioglitazone-treated rats compared with vehicle-treated control rats. Conclusions-Pioglitazone

Apurinic/apyrimidinic endonucelase 1 maintains adhesion of endothelial progenitor cells and reduces neointima formation

“…However, in this study that uses EPCs, it is difficult to induce detrimental effects on cells, including the adhesion ability, with cytokines, including a combination of IL-1␤, interferon-␥, and TNF-␣. We have confirmed that cellular damage/apoptosis can be induced in vascular smooth muscle cells, and CECs can be induced by these cytokines (3). Cytokines such as TNF-␣ have been reported to have both beneficial and detrimental effects on certain cell types including mesenchymal stem cells and EPCs (40,46).…”

Peroxisome Proliferator-Activated Receptor .GAMMA. and Cardiovascular Diseases

“…[21][22][23][24] Furthermore, TZDs induce apoptosis of VSMCs via p53 and Gadd45. 25,26 Angiotensin II (AngII) plays an important role in vascular remodeling via the AngII type 1 receptor (AT1R) and accelerates atherosclerosis. Although AngII induces transcriptional suppression of PPARγ, activation of PPARγ inhibits AT1R gene expression at a transcriptional level in VSMCs.…”

New targets for PPARγ in the vessel wall: implications for restenosis

“…The region between À234 and À81, therefore, contains critical elements required for activation of the PPARg ligands inhibit intimal hyperplasia in rat models of restenosis after balloon injury in both insulin-resistant and insulin-sensitive animals. 1,[27][28][29][30] Concomitant with the phenotypic shift from quiescent VSMC resident in the uninjured vessel wall to proliferating VSMC present in the neointima, there is a substantial upregulation of PPARg expression. 3,9 High-level expression of functional PPARg in intimal VSMC, therefore, provides an attractive therapeutic target to exploit the antiproliferative and proapoptotic properties of PPARg ligands.…”