Abstract 3805: Hemodynamic and Molecular Effects of Resistin Overexpression on Cardiovascular Function In Vivo
Our group has recently shown that resistin, an adipocytokine involved in insulin resistance, was highly expressed in left ventricle (LV) of rat models of diabetes mellitus. Adenoviral overexpression of resistin induced a hypertrophic response in neonatal rat cardiomyocytes and decreased contractility in adult rat cardiomyocytes. To investigate the in vivo effects of resistin on LV hypertrophy and hemodynamics, we gave neonatal rats an intracardiac injection of adenovirus expressing resistin (Ad.Retn, n=7) or beta-galactosidase (Ad.β-gal, n=4) with a CMV promoter, to allow long-term protein expression. On LV anterior wall thickness measure by echocardiography, the Retn group showed a mild but statistically significant hypertrophic response at 2, 3 and 4 months compared to the β-gal group (0.24 ±0.02 cm vs. 0.20 ± 0.005 cm at 3 months, p<0.05). At 5 and 6 month, the β-gal group showed a similar, likely age-related, wall thickening of the left ventricle. The Retn group displayed a trend to reduced LV shortening fraction and ejection fraction, with increased LV end-systolic volume throughout the study. At end of study (6 months), invasive hemodynamics were measured by pressure-volume loop analysis. The Retn group had a higher maximal LV pressure than the β-gal group (139 ± 13.0 vs. 123 ± 6.3 mmHg, p<0.05), higher minimal LV pressure (12.7 ± 3.0 vs. 2.6 ± 1.4 mmHg, p<0.01), and higher LV end-diastolic pressure (18.0 ± 2.9 vs. 7.7 ± 4.2 mmHg, p<0.01). Invasive contractility parameters did not differ. End-systolic and end-diastolic pressure-volume relationships of the left ventricle were obtained during inferior vena cava occlusion. A steeper end-diastolic pressure-volume curve was found in the Retn group, indicating a higher passive stiffness of the left ventricle (P= 0.1). The level of expression of the dimeric resistin protein was increased in the Retn group by 2.3 fold (p<0.05). There was a significant increase in the phospholamban/SERCA2a ratio in the Retn group suggesting abnormal calcium handling associated with myocardial dysfunction. Our studies also showed an increased level of iNOS and a decreased level of eNOS in the Retn group. Our data support a role for resistin in direct myocardial dysfunction associated with insulin resistance.