Abstract 206: PPARγ Deficiency Causes Aortic Stiffness and Dysregulated Elastin Turnover

Abstract

PPARγ, a nuclear receptor that regulates adipocyte development and glucose homeostasis, is the molecular target of a class of insulin-sensitizing drugs. Loss-of-function mutations in PPARG gene are implicated in human hypertension and PPARγ agonists decrease blood pressure both in animal models and human patients. We have previously generated mice with varying Pparg expression created by modifying its 3′-UTR sequence, and concluded an inverse relationship between PPARγ expression level and blood pressure. Interestingly, mice with extremely low PPARγ expression exhibited an increase in systolic blood pressure without significant change in diastolic blood pressure, ultimately causing a significant increase in pulse pressure. Thus, we hypothesized that PPARγ deficiency impairs aortic elasticity, resulting in the increase in pulse pressure. Aortic pulse wave velocity (PWV) was significantly increased in PPARγ hypomorphic mice, suggesting that aortas of PPARγ hypomorphic mice were stiffer than those of wild-type mice. The measurement of mechanical property by atomic force microscope (AFM) showed higher tissue rigidity in the aorta of PPARγ hypomorphic mice. Expression of elastin in aortas was significantly decreased, and negatively correlated with aortic PWV in PPARγ hypomorphic mice. This was accompanied by increased elastin fiber breaks, elastolytic activity, and expressions of MMP-9 in aortas of PPARγ hypomorphic mice. The elevated PWV in PPARγ hypomorphic mice was ameliorated after treatment of PPARγ agonist. Together, our results suggest that PPARγ deficiency impairs elasticity in aorta and underscore the importance of PPARγ in the regulation of blood pressure and vascular reactivity.