Abstract 14898: Cardiac-Restricted Overexpression of Liver X Receptor Attenuates Adverse Cardiac Remodeling
Background - Liver X Receptor (LXR) agonists have been studied for their potential antihypertrophic effects on the heart. However, LXR agonists elicit severe systemic side-effects such as hypertriglyceridemia, lipogenesis and hepatic steatosis, therefore their use is substantially limited. To circumvent these unwanted systemic effects, we generated a transgenic mouse with cardiomyocyte-specific overexpression of LXR and evaluated whether cardiospecific LXR activation would inhibit adverse left ventricular (LV) remodeling in a model of cardiac hypertrophy.
Methods and Results - We cloned murine LXRα behind the alpha-myosin heavy chain (αMHC) promoter to create transgenic (TG) mice and transgene-negative littermates (CON). TG mice exhibited a myocardial overexpression of LXRα mRNA and protein of approximately 300- and 10-fold, respectively. Mice underwent transverse aortic constriction (TAC) for 5 weeks to induce LV hypertrophy. TAC caused a 54% increase in LV weight in CON, but only 27% in TG mice (P<0.001). LV hypertrophy was also attenuated in TG mice in an alternative model of angiotensin II-induced hypertrophy (P<0.05). Echocardiography revealed a significant decrease in % fractional shortening in CON vs TG mice after TAC (-12% vs -4%, P< 0.001). Furthermore, myocardial fibrosis was increased 4.4-fold in CON after TAC, whereas fibrosis was not increased in TG (P<0.05). After TAC, typical changes in fetal gene expression were observed in CON, but to a lesser extent in TG mice: α/βMHC ratio -4.7 vs -1.2 (P<0.001), ANP +6.3 vs 3.9 (P<0.05), BNP +4.0 vs 1.8 (P<0.05), and α-smooth muscle actin +7.7 vs 4.0 (P<0.001). Gene profiling of the whole heart transcriptome revealed that genes of various metabolic clusters were differentially expressed in TG mice, and changes in these pathways may underpin the cardioprotective effects of LXR.
Conclusion - Our results indicate that cardiac-restricted overexpression of LXR attenuates LV hypertrophy, fibrosis and remodeling with concomitant preservation of cardiac function. Herein, we provide insight into a novel therapeutic approach for treating pathological cardiac hypertrophy and progression to heart failure.
- © 2011 by American Heart Association, Inc.