Abstract

Obesity is a major risk factor for the development of cardiovascular diseases including cardiac hypertrophy. Mice fed with a high fat diet (HFD) become obese after 7-8 weeks and eventually develop cardiac hypertrophy. Yet, the time course of the development of the diet-induced cardiac hypertrophy is largely unknow. To study the initial events leading to hypertrophy we fed mice (C57BL/6) with a HFD (60% fat, 20% proteins and 20% carbohydrates) and measured cardiac dimension and function by echocardiography-doppler after 8 and 12 weeks on this diet. We also determined the mRNa expression for hypertrophic markers such as BNP and RCAN1.4 and since obesity induces the expression of NADPH oxidase in several tissues, we also measured the expression of NOX2 and NOX4, the two isoforms of NAPDH oxidase expressed in the heart. We found that after 8 weeks on a HFD, mice show normal cardiac dimensions but a decrease in the ratio of the peak velocity in early diastole (Early filling: E) to peak velocity flow in late diastole (Active filling: A) (E/A ratio), indicating the presence of diastolic dysfunction. By 12 weeks E/A ratio is normalized (pseudo normalization) but there is a significant increase in the thickness of the interventricular septum, the left ventricular posterior wall and the heart weight / tibia length ratio, all signals of hypertrophy. At the molecular level, other signs of hypertrophy were significant increases in the mRNa expression of BNP and RCAN1.4. We also found an increase in the expression of NOX4 from 8 weeks but NOX2 expression was unchanged. Until 12 weeks, however, there were no signs of oxidative stress such as a decrease in total glutathione concentration or GSH/GSSG ratio or an increase in carbonylated proteins in the heart. These results suggest that cardiac hypertrophy develops at 12 weeks as a compensatory response to the diastolic dysfunction induced by the HFD. Redox signaling involving NOX4 may underlie this response