Abstract 15783: The Novel Liver X Receptor Agonist AZ876 Attenuates Pathological Cardiac Hypertrophy in Mice Without Causing Hypertriglyceridemia and Hepatic Steatosis
Purpose: Liver X Receptors (LXR) transcriptionally regulate inflammation, metabolism and immunity. Pharmacological activation of LXRs confers beneficial effects in the cardiovascular system. However, current LXR agonists elicit severe systemic side effects such as hypertriglyceridemia and hepatic steatosis, therefore limiting their therapeutic use. AZ876 is a novel high-affinity LXR agonist previously shown to inhibit progression of atherosclerosis in mice without incurring the aforementioned adverse effects. Whether AZ876 exerts additional protection in the heart remains to be explored. Therefore, we investigated the effects of AZ876 on adverse cardiac remodeling processes in a murine model of pressure overload.
Methods: C57Bl6/J mice underwent transverse aortic constriction (TAC) to induce left ventricular (LV) hypertrophy, or sham operation, for 6 weeks. During this period, AZ876 (AZ, 20 μmol/kg/day) and vehicle (veh) were administered in chow (N=7-10/group). Cardiac function was assessed with echocardiography and hemodynamic catheterization.
Results: AZ treatment reduced cardiac hypertrophy caused by TAC as heart weight increased by 66% in TAC-veh, but only 44% in TAC-AZ mice (P<0.05). AZ treatment attenuated TAC-induced declines in systolic function as fractional shortening was significantly decreased in veh compared to AZ (-15% vs -7%, P< 0.001). LV end-diastolic pressure was significantly elevated in TAC-veh, but not in AZ (P<0.05). Molecular hypertrophic markers were present in both TAC groups, but to a lesser extent in AZ-treated mice: ANP 13.9 vs 5.2, βMHC 7.6 vs 3.9, Rcan1 8.8 vs 4.5, and Acta1 15.3 vs 9.7 (P<0.05). Furthermore, AZ diminished the development of myocardial fibrosis (4.5-fold versus 2.8-fold for TAC-veh and TAC-AZ respectively, P<0.001), which was also evidenced by reduced Tgfβ, Ctgf, Timp1 and Fstl3 gene expression (P<0.05). Plasma triglycerides and liver weight were unaltered by AZ.
Conclusion: AZ876 treatment attenuated cardiac hypertrophy, fibrosis and dysfunction in mice following pressure overload. Importantly, these beneficial effects occurred in the absence of increased plasma triglycerides and liver weight. AZ876 should thus be further explored for its cardioprotective potential.
- © 2013 by American Heart Association, Inc.