Abstract 16005: Cardiomyopathy in a Rat Model of High-Fat-Diet-Induced Obesity: Effects of Left Ventricle and Myocyte Functional Performance, [Ca2+]i Transient Response and Beta-Adrenergic Modulation
Background: Obesity is associated with the development of cardiomyopathy. However, the mechanism is unclear. Although recent evidence links altered β-adrenergic regulation with obese (OB) cardiomyopathy, the alterations and functional effects of cardiac β-adrenergic receptor (AR) systems have not been systematically evaluated. Whether isolated OB causes intrinsic cardiomyocyte dysfunction is unclear. We tested the hypothesis that OB rats would demonstrate impaired LV myocyte function and [Ca2+]i regulation with desensitization of cardiac β-adrenergic signaling. Downregulation of myocyte β1-AR and SERCA2a, but upregulation of β3-AR, are important contributing causes.
Methods: We simultaneously evaluated LV and myocyte function and the expression of myocyte subtypes of β-adrenergic receptors (AR) and SERCA2a in male SD rats of 8 OB (fed with a high-fat diet, 45% of calories from fat, for 12 months) and 8 controls. Cardiac histopathological alterations were determined.
Results: Compared with controls, OB had similar heart rate, LV systolic blood pressure and ejection fraction, but significantly decreased LV contractility (EES) (0.8 vs 1.1 mmHg/μl) and 37% reduced DV/dtmax with increased LV time constant of relaxation (15.0 vs 9.6 ms). Importantly, these LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax, 92.5 vs 130.2 μm/sec), relaxation (dR/dtmax, 79.2 vs 129.1 μm/sec) and [Ca2+]iT (0.20 vs 0.26). In OB, myocyte SERCA2a (0.43 vs 0.56), β1- (0.37 vs 0.63) and β2-AR protein levels significantly decreased by 23%, 41% and 40%, respectively, but β3-AR (0.68 vs 0.31) increased by 119%. Compared with controls, isoproterenol (10-8 M) produced significantly smaller increases in dL/dtmax (31% vs 67%) and dR/dtmax (21% vs 52%), but β3 agonist of BRL-37344 (10-8 M) caused significantly greater decreases in dL/dtmax (17% vs 8%) and dR/dtmax (27% vs 9%). Histological evidence showed LV tissue disorganization and fibrosis.
Conclusions: Obesity downregulates LV myocyte β1- and β2-AR and SERCA2a, but upregulates β3-AR, leading to myocyte systolic and diastolic dysfunction with impaired [Ca2+]i regulation and β-adrenergic modulation, thus apparently preceding the development of OB cardiomyopathy.
- © 2013 by American Heart Association, Inc.