Abstract 12900: Pressure Overload Induces Hypertrophy and Impaired Cardiac Function in Long-chain Fatty Acid Transporter CD36 Knockout Mice

Background: CD36 is an important transporter of long-chain fatty acids (LCFA) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake is compensatorily increased, and are often accompanied by cardiomyopathy. However, its molecular mechanisms and functional role of CD36 in the myocardium remain unknown. Aim: To explore the pathophysiological role of CD36 in the heart, we analyzed CD36 knockout (KO) mice at the baseline and under the pressure overload. Methods: Using wild type (WT) and KO mice at 7-10 weeks(wks) old, we performed transverse aortic constriction (TAC) to generate pressure overload and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses were performed at 2 and 4 wks after TAC. Results: At the baseline, there were no significant differences in left ventricular wall thickness and left ventricular fractional shortening (LVFS) between KO and WT mice. By applying a TAC for 4 wks, the survival rate was significantly lower in KO than that in WT mice (30.0% vs 85.7%, P=0.0018). At 2wks after TAC, KO mice showed significantly higher heart weight (HW) to tibia length (TL) ratio than that of WT (HW/TL;10.4±1.0 mg/mm vs 8.4±0.8 mg/mm, P=0.003). We also observed significantly larger cross-sectional area of cardiomyocytes in KO than that of WT, suggesting that hypertrophic response of KO mice was more marked than WT mice. KO mice with TAC showed more enhanced phosphorylation of S6 ribosomal protein compared to WT mice with TAC, suggesting that protein synthesis in KO mice was more enhanced than that in WT mice. KO mice with TAC showed increased lung weight (LW) to TL ratio and singnificantly reduced LVFS rather than WT with TAC (LW/TL; 13.9±5.7mg/mm vs 9.2±2.0mg/mm, P=0.069, FS; 24.1±1.1% vs 34.9±3.0%, P=0.00007), suggesting that pressure overload induced early systolic dysfunction in KO mice even at 2 wks after TAC, when WT mice showed compensatory cardiac hypertrophy. Conclusion: The LFCA transporter CD36 plays important roles regulating cardiac hypertrophy and function, and deficiency of CD36 causes cardiac dysfunction in the pressure overload condition.