Development of Decompensated Dilated Cardiomyopathy Is Associated With Decreased Gene Expression and Activity of the Milrinone-Sensitive cAMP PhosphodiesterasePDE3A

• DOI: 10.1161/01.cir.96.9.3116
• Publication Date: 2012-06-12T00:41:02Z
• Authors: Carolyn J. Smith; Raymond Huang; Dong Sun; Sidonnie Ricketts; Carl Hoegler; Jia-Zhen Ding; Richard A. Moggio; Thomas H. Hintze
• Keywords: Contractility; Milrinone; Phosphodiesterase 3; Dilated Cardiomyopathy; Glyceraldehyde 3-phosphate dehydrogenase

Background Phosphodiesterase III (PDE3) inhibitors are inotropic agents used to treat congestive heart failure (CHF) and less effective in patients with severe CHF. Little is known about relative changes PDE3 activity or gene expression during the evolution of cardiomyopathy. Methods Results In present study, we evaluated temporal PDE3A before after pacing-induced CHF nine mongrel dogs. Three weeks left ventricular (LV) pacing produced LV end-diastolic pressures 15±1.7 mm Hg, whereas overt at 4 5 was associated 24±1.7 Hg; prepacing values were 6.6±0.6 Hg. Total RNA isolated from tissues analyzed on Northern blots; 10 unpaced normal hearts served as tissue controls. Signals for mRNAs (7, 8, kb) PDE4D (7.6 normalized against glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ) ribosomal 18S RNA. Before onset CHF, / ratios not different between control 3-week paced groups. contrast, all selectively reduced by 52%, /18S 70% P <.05) CHF; (or 18S) unchanged. four dogs also processed isolate cytosolic microsomal membrane protein cAMP assays. a significant 54% reduction but activity. Conclusions Selective downregulation may account part ineffectiveness milrinone treatment