Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice

OBJECTIVE: We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse model and to test if high cholesterol or high triglyceride is responsible for the hyperlipidemia-induced cardiac dysfunction. METHODS AND RESULTS: To determine the effect of cholesterol-enriched diet on cardiac performance and oxidative/nitrosative stress, wildtype and human apoB100 transgenic mice were fed a 2% cholesterol-enriched or a normal diet for 18 weeks. Serum cholesterol and LDL-cholesterol levels were significantly elevated only in the cholesterol-fed apoB100 transgenic mice, while serum triglycerides were increased in the transgenic mice fed a normal diet. Cholesterol-enriched diet significantly increased cardiac superoxide generation and NADPH oxidase expression and activity in apoB100 mice but not in wildtypes. Cardiac NO content and NO synthase activity did not change in either group. As assessed in isolated working hearts, aortic flow was significantly decreased only in apoB100 transgenic mice fed a cholesterol-enriched diet. The peroxynitrite decomposition catalyst FeTPPS attenuated the decrease in aortic flow in cholesterol-fed apoB100 mice. Immunohistochemistry showed elevated nitrotyrosine in the hearts of apoB100 mice fed the cholesterol-enriched diet. CONCLUSIONS: We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.