Abstract 319: Cardiomyocyte-specific Overexpression of Type 5 Phosphodiesterase Impairs Postinfarction Myocardial Function and Left Ventricular Remodeling.
Background: Cyclic guanosine monophosphate (cGMP), a second-messenger regulator of cardiovascular function, modulates acute and chronic stress responses in the heart. Myocardial cGMP levels are determined by the balance between production via guanylate cyclases and hydrolysis via phosphodiesterases (PDEs). To better understand the role of cGMP hydrolysis in the myocardial response to hemodynamic challenge, we generated transgenic mice with cardiomyocyte-specific overexpression of a cGMP-specific PDE (PDE5TG) and compared the LV remodeling response to myocardial infarction (MI) with wild-type littermates (WT).
Methods: PDE5 expression was examined in hearts of WT and PDE5TG using qRT-PCR, immunoblot analysis, confocal microscopy, and measurement of cGMP hydrolysis. Cell shortening and calcium (Ca) handling were determined in paced cardiomyocytes from adult PDE5TG (n = 7) and WT (n = 5). LV function and dimensions, as well as hemodynamic parameters, were compared in anesthetized PDE5TG and WT using echocardiography and pressure-volume catheter techniques at baseline (n = 20) and 10 weeks after proximal LAD ligation (n = 16).
Results: The PDE5 transgene was selectively but homogeneously expressed in cardiomyocytes of PDE5TG and resulted in a 10-fold increase in cGMP hydrolysis. Ca transients, Ca currents and cell shortening did not differ between PDE5TG and WT cardiomyocytes and baseline echocardiographic and hemodynamic parameters were comparable. After MI, cardiac dimensions were larger in PDE5TG than in WT and for a similar infarct size, LV end-diastolic volumes and pressures were larger in PDE5TG than in WT (81 ± 15 vs 50 ± 20 μL, P < 0.01 and 9 ± 5 vs 4 ± 4 mmHg, P < 0.05 respectively), and isovolumic relaxation was more prolonged (11 ± 2 vs 8 ± 3 ms, P = 0.01). Preload-recruitable stroke work and maximal elastance tended to be lower in PDE5TG than in WT (P = 0.07 and 0.05, respectively). After MI, extravascular lung water weight was greater in PDE5TG than in WT (P < 0.05).
Conclusions: Cardiomyocyte-specific overexpression of PDE5 does not alter baseline cardiac structure or function, but significantly impairs systolic and diastolic function and LV remodeling after MI. Myocardial PDE signaling is an important novel target in post-infarction heart failure.