Abstract 510: Deficiency of Cardiac Lypoprotein Lipase Prevents Normal Compensation to Hypertensive Stress
Although hearts adjust to pressure overload hypertrophy by increased glucose uptake and oxidation, this occurs in the presence of continued uptake and use of fatty acid (FA), the major source of cardiac energy. We created cardiac lipoprotein lipase deficient mice (hLpL0) and showed that these mice, with loss of lipoprotein-derived FA, are unable to survive aortic constriction. We, therefore, tested whether hLpL0 mice have normal cardiac compensation to two types of hypertensive stress, chronic angiotensin II (Ang II) treatment and DOCA-salt hypertension. In control (CTL) mice, Ang II (4mg/kg/day, s.c. 2 weeks) treatment caused hypertension (~170mmHg), hypertriglyceridemia and elevated plasma free FA. Ang II reduced cardiac PDK4, FATP1 and ACO mRNA expression and increased cardiac 2-deoxyglucose (DG) uptake (~4 fold), suggesting increased glucose and reduced FA utilization. Ang II-treated CTL mice had compensated concentric cardiac hypertrophy with reduced left ventricular diastolic diameter (LVDd) and preserved % fractional shortening (%FS). In contrast, young (10–12 weeks) hLpL0 mice, whose cardiac function is normal in the absence of stress, had a similar degree of Ang II-induced hypertension and hypertrophy but developed cardiac dysfunction: decreased %FS and increased lung/body weight ratio with unchanged LVDd. HLpL0 mice had greater basal 2-DG uptake, which was not increased further by Ang II. DOCA-salt treatment (3 weeks) also induced hypertension (~160mmHg) and cardiac hypertrophy in CTL mice with no significant changes in plasma lipids and cardiac PDK4, FATP1 and ACO mRNA expression. LVDd was increased with preserved %FS in CTL mice. In hLpL0 mice with similar hypertension had reduced cardiac systolic function, a >20% reduction in %FS (n=4, p=0.003). In contrast to CTL mice, DOCA-salt treatment did not significantly increase left ventricular mass in hLpL0 mice. Thus, loss of cardiac LpL, a genetic intervention that does not alter albumin-associate FA uptake by hearts, prevents normal cardiac compensation to hypertensive stress. Despite marked increases in glucose uptake, under stress hearts also require lipoprotein-derived FA.