Extracellular Matrix Remodeling in the Heart of the Homocysteinemic Obese Rabbit

Despite the strides made toward understanding cardiac abnormalities in obesity-induced hypertension, the composition and concentration of cardiac extracellular matrix (ECM) components resulting from diet-induced obesity are largely unknown. Previous studies from our laboratory have demonstrated differential expression of collagens, growth factors, and homocysteine (Hcy) in pressure overload models of cardiac hypertrophy. The hypothesis of the present study was that left ventricular hypertrophy (LVH) from the combined pressure and volume overload of obesity induced cardiac fibrosis in part by increasing Hcy, increasing transforming growth factor-β1 (TGF-β1), and decreasing decorin. Using the rabbit model, we examined the changes in cardiac collagen accumulation, plasma Hcy, left ventricular (LV) TGF-β1, and LV decorin after 12 weeks of developing obesity. Cardiac fibrosis was analyzed by trichrome stain for collagens. Total collagens types I and III, TGF-β1, and decorin were analyzed in tissue homogenates by immunoblots and quantitated with a densitometer. After 12 weeks, rabbits eating a high-fat diet had greater body weight (5.38 ± 0.3 kg v 3.73 ± 0.6 kg) and greater LV weight (5.08 ± 0.05 g v 3.86 ± 0.17 g) compared with lean rabbits. Heart rate was also significantly higher in obese than in lean rabbits (221 ± 8 v 173 ± 5 beats/min). Plasma concentrations of circulating Hcy were 16.9 ± 2.4 μmol/L and 24.3 ± 1.8 μmol/L in lean and obese rabbits, respectively. Compared with lean rabbits, obese rabbits had increased interstitial and perivascular collagen, a 4-fold increase in the medial/lumen ratio of coronary vessels, a 1.75-fold increase in cardiac collagen I, and a 1.5-fold increase in cardiac collagen III levels. Levels of TGF-β1 were increased 1.75-fold, whereas decorin levels were significantly reduced in obese compared with lean rabbits. In conclusion, a high-fat diet, even over a period as short as 12 weeks, causes fibrosis in coronary vessels as well as accumulation of collagen in the cardiac interstitium. The accumulation of cardiac collagen was associated with induction of Hcy and TGF-β1 and with suppression of decorin.