Antiinflammatory and Antiarteriosclerotic Effects of Pioglitazone

Abstract

Abstract-Peroxisome proliferator-activated receptor-␥ (PPAR␥) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPAR␥ activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N -nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPAR␥ ligand) in this rat model to determine whether PPAR␥ activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPAR␥ activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes).

Inhibition of Vascular Angiotensin-Converting Enzyme by Telmisartan via the Peroxisome Proliferator-Activated Receptor .GAMMA. Agonistic Property in Rats

“…The telmisartan dose of 1 mg/kg per day in the present study may have weakly stimulated PPARγ. A typical PPARγ ligand, pyoglitazone, significantly reduced vascular ACE activity in a N ω -nitro-L-arginine methyl esterinduced hypertensive model (27), and the dose of telmisartan also reduced vascular ACE activity in the present study. On the other hand, Imayama et al (28) demonstrated that pyoglitazone and telmisartan, a partial PPARγ agonist, significantly reduced AT1 receptor expression in cultured rat vascular smooth muscle cells, but that the non-PPARγ agonists olmesartan and candesartan did not.…”

Conditional Knockout of Macrophage PPARγIncreases Atherosclerosis in C57BL/6 and Low-Density Lipoprotein Receptor–Deficient Mice

“…41 In addition, PPAR␥ agonists inhibit CCR2 expression in monocytes and atherosclerosis development in rats. 42,43 Thus, PPAR␥-mediated CCR2 expression by macrophages may be an important pathway in atherogenesis and provides a novel therapeutic target for prevention or treatment of atherosclerosis.…”

The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis†

“…However, it is unclear if the beneficial effects of these agents are based primarily on decreasing insulin resistance, because the PPAR␥ agonists have anti-inflammatory, anti-fibrotic as well as other metabolic activities. 13,14 The aim of the current study was to characterize the biochemical, metabolic, and histological changes that occur after pioglitazone is discontinued in a cohort of patients who demonstrated significant improvement in these parameters during therapy.…”