Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model
Abstract
Aim:Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits.
Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg-1·d-1, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes.
Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R2=0.74, P<0.01) and global LV function (R2=0.47, P<0.01).
Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure.
Keywords:
sildenafil; PDE5 inhibitor; T-tubule; pressure overload; left ventricular remodeling; left heart failure
Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg-1·d-1, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes.
Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R2=0.74, P<0.01) and global LV function (R2=0.47, P<0.01).
Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure.