Abstract P202: Role of Lipid Peroxidation--Derived Carbonyls in Left Ventricular Hypertrophy

Abstract

Pathological left ventricular hypertrophy (LVH) is a key factor in the development of heart failure and cardiomyopathy. It is characterized by increased oxidative stress however the mechanisms by which it affects pathological LVH remain unclear. Because the effects of reactive oxygen species are mediated by products of lipid peroxidation, we hypothesize that myocardial injury induced by LVH is mediated by lipid carbonyls, which form covalent adducts with proteins that induces autophagy. To test this hypothesis, we examined the role of aldose reductase (AKR1B3; AR) an enzyme that catalyzes the detoxification of lipid carbonyls in modulating the cardiac stress responses in WT and AR-null mice hearts that were subjected to transverse aortic constriction (TAC). Two weeks after the TAC cardiac enlargement in the AR-null TAC mice was more prominent compared with WT TAC mice. Hemodynamic analysis of the AR-null TAC mice demonstrated left ventricular dilatation and severe contractile dysfunction compared with WT TAC mice. Expression levels of molecular marker for hypertrophy (ANF) increased 2-3 fold in AR-null TAC compared with the WT-TAC. Western blot analysis of the heart homogenates using anti-4 hydroxy-trans-2-nonenal (HNE) antibody showed that the formation of HNE-protein adduct (300KDa) increased 100-fold and the bands corresponding to molecular weights of 75KDa, 40KDa increased 2 to 3-fold after the TAC in WT hearts and the intensity of these bands in AR-null TAC hearts was significantly higher compared with WT TAC. Immuno-blot analysis of the heart homogenates revealed an increase in the LC3-I to LC3-II conversion in banded hearts compared with sham-operated controls and the autophagic activity was more prominent in the AR-null compared to the WT banded hearts. Isolated adult cardiomyocytes from WT and AR-null hearts perfused with HNE resulted in an increase in autophagy and the increase in autophagic activity was robust in AR-null than in WT myocytes. These data establish that TAC-induced hypertrophy increases protein-HNE-adduct formation and autophagic activity and the deletion of akr1b3 gene exacerbates these responses to pressure overload.