Myocardial Remodeling Is Controlled by Myocyte-Targeted Gene Regulation of Phosphodiesterase Type 5

• Published in: Journal of the American College of Cardiology Vol. 56; no. 24; pp. 2021 - 2030
• Main Authors: Zhang, Manling, MD, Takimoto, Eiki, MD, PhD, Hsu, Steven, MD, Lee, Dong I., PhD, Nagayama, Takahiro, PhD, Danner, Thomas, Koitabashi, Norimichi, MD, PhD, Barth, Andreas S., MD, Bedja, Djahida, MS, Gabrielson, Kathleen L., PhD, Wang, Yibin, PhD, Kass, David A., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 07.12.2010; Elsevier; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiovascular; cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics; Disease; Gene Expression Regulation, Enzymologic; Genes; Heart failure; Histology; Humans; Internal Medicine; Kinases; Medical sciences; Mice; Monocytes - metabolism; Mortality; Myocytes, Cardiac - metabolism; Nitric oxide; phosphodiesterase-5; pressure overload; protein kinase G; Proteins; Rodents; Signal Transduction; Studies; transgenic mouse models; Ventricular Remodeling - genetics; cyclic guanosine monophosphate; cGMP; MHC; LV; doxycycline; pressure overload; PDE; protein kinase G; transgenic; left ventricular; heart failure; myosin heavy chain; cyclic GMP; phosphodiesterase-5; DOX; PKG; ECM; trans-aortic constriction; TGF; TG; TAC; phosphodiesterase; transforming growth factor; extracellular matrix; transgenic mouse models; Vascular remodeling; Regulation(control); Gene; Enzyme; 3',5'-Cyclic-GMP phosphodiesterase; Myocardium; Hydrolases; Esterases; Phosphoric diester hydrolases; Circulatory system; Cardiology; Myocyte
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2010.08.612

Objectives We tested the hypothesis that bi-directional, gene-targeted regulation of cardiomyocyte cyclic guanosine monophosphate–selective phosphodiesterase type 5 (PDE5) influences maladaptive remodeling in hearts subjected to sustained pressure overload. Background PDE5 expression is up-regulated in human hypertrophied and failing hearts, and its inhibition (e.g., by sildenafil) stimulates protein kinase G activity, suppressing and reversing maladaptive hypertrophy, fibrosis, and contractile dysfunction. Sildenafil is currently being clinically tested for the treatment of heart failure. However, researchers of new studies have questioned the role of myocyte PDE5 and protein kinase G (PKG) to this process, proposing alternative targets and mechanisms. Methods Mice with doxycycline-controllable myocyte-specific PDE5 gene expression were generated (medium transgenic [TG] and high TG expression lines) and subjected to sustained pressure overload. Results Rest myocyte and heart function, histology, and molecular profiling were normal in both TG lines versus controls at 2 months of age. However, upon exposure to pressure overload (aortic banding), TG hearts developed more eccentric remodeling, maladaptive molecular signaling, depressed function, and amplified fibrosis with up-regulation of tissue growth factor signaling pathways. PKG activation was inhibited in TG myocytes versus controls. After establishing a severe cardiomyopathic state, high-TG mice received doxycycline to suppress PDE5 expression/activity only in myocytes. This in turn enhanced PKG activity and reversed all previously amplified maladaptive responses, despite sustained pressure overload. Sildenafil was also effective in this regard. Conclusions These data strongly support a primary role of myocyte PDE5 regulation to myocardial pathobiology and PDE5 targeting therapy in vivo and reveal a novel mechanism of myocyte-orchestrated extracellular matrix remodeling via PDE5/cyclic guanosine monophosphate–PKG regulatory pathways