Abstract 15805: Pioglitazone Attenuates Calcification of the Aortic Valve Induced by Hypercholesterolemia
Vascular calcification and calcific aortic valvular stenosis (CAVS) appear to involve multiple signaling pathways. Peroxisome proliferator-activated receptor-gamma (PPARγ) affects a cluster of genes and may protect against calcification by several mechanisms. The goal of this study was to test the hypothesis that activation of PPARγ by administration of pioglitazone inhibits calcification of the aortic valve and aorta in hypercholesteremic mice. LDLr-/-/ApoB100 (LA) mice were given a western-type diet (WD) for 6 months, and treated with pioglitazone (Pio, 20 mg/kg/day). Pioglitazone greatly increased expression of Rbp7, a target gene of PPARγ (chow, 1±0.2; WD, 0.9±0.4; WD+Pio, 16±7*; mean±SE, * = p<0.05 vs chow or WD) in aorta and attenuated inflammation, with reduction of serum amyloid A in plasma and of TNFα expression in aorta (chow, 1±0.1; WD, 1.6±0.2*; WD+Pio, 1±0.1**, * = p<0.05 vs chow, ** = p<0.05 vs WD). Pioglitazone greatly attenuated deposition of lipids (% positive area by oil red O) in the aortic valve (chow, 13.6±0.7; WD, 32.3±1.5*; WD+Pio, 18.7±1.5**) and attenuated calcification in the aortic valve (% staining with alizarin red) (chow, 0.3±0.1; WD, 1.4±0.3*; WD+Pio, 0.6±0.2**). Calcification in aortic root and ascending aorta was not reduced by pioglitazone, despite a reduction of bone morphogenetic protein 2 mRNA levels (which implies inhibition of a pro-osteogenic pathway) in aorta. In addition, pioglitazone reduced levels of active caspase-3 (% positive area, immunostaining) in aortic valve (chow, 9.4±3.5; WD, 16.4±3.5*; WD+Pio, 7.2±1.0**), which implies inhibition of cell death by pioglitazone. Pioglitazone prevented a small, but statistically significant, decrease in aortic valve function, determined with echocardiography. In summary, the findings suggest that PPARγ activation protects against lipid deposition and calcification of the aortic valve, in part by inhibition of osteogenic pathways and cell death.
- © 2011 by American Heart Association, Inc.