Abstract 133: Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction Are Exacerbated in Heterozygous Carnitine Palmitoyltransferase 1b--Deficient Mice
Carnitine palmitoyltransferase 1 (CPT1) is a primary rate-limiting enzyme that controls the entry of long-chain fatty acids into the mitochondrial matrix. CPT1b is the predominant isoform in the heart essential for myocardial fatty acid oxidation (FAO). Inhibition of myocardial FAO by specific CPT1 inhibitors has been proposed to be cardioprotective, but with mixed results from animal and human studies. To gain more specific insights, the present study investigates the effect of CPT1b deficiency in mice subjected to transverse aorta constriction (TAC)-induced pressure-overload. Because homozygous knockout of CPT1b causes embryonic lethality, we used the overtly normal heterozygous CPT1b knockout (CPT1b+/-) mice and their wild type (WT) littermates for the study. Under a severe pressure-overload condition, CPT1b+/- hearts showed substantially increased mortality compared with WT hearts. Under a milder pressure-overload condition, CPT1b+/- mice showed more pronounced cardiac hypertrophy than WT mice. Echocardiographic measurement revealed greater increases of posterior wall thickness at diastole, left ventricular (LV) internal dimension at systole and LV mass in CPT1b+/- than in WT mice. Stroke volume, ejection fraction and fraction shorting were also further decreased in CPT1b+/- mice. Based on assessments of heart-weight to body-weight ratio, molecular markers of cardiac hypertrophy, the cross-sectional area of cardiomyocytes, fibrosis and cardiomyocyte apoptosis, cardiac pathological hypertrophy was more pronounced in CPT1b+/- than in WT mice. Transmission electron microscope assessment revealed a reduced mitochondrial volume in CPT1b+/- compared with WT hearts after TAC. CPT1b+/- heart sections exhibited dramatic myocardial lipid accumulation with numerous lipid droplets. Moreover, CPT1b+/- hearts exhibited substantially elevated triglycerides and ceramide contents compared with WT hearts. Therefore, we conclude that CPT1b deficiency is detrimental to the heart under the pressure-overload condition with exacerbated cardiac dysfunction and progressive development of pathological hypertrophy due to lipotoxicity, thus cautions should be taken in evaluating CPT1b as a therapeutic target for heart disease.
- © 2011 by American Heart Association, Inc.