TY - JOUR
T1 - Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5
AU - Zhang, Manling
AU - Takimoto, Eiki
AU - Hsu, Steven
AU - Lee, Dong I.
AU - Nagayama, Takahiro
AU - Danner, Thomas
AU - Koitabashi, Norimichi
AU - Barth, Andreas S.
AU - Bedja, Djahida
AU - Gabrielson, Kathleen L.
AU - Wang, Yibin
AU - Kass, David A.
N1 - Funding Information:
Supported by National Institutes of Health–National Heart, Lung, and Blood Institute grants HL-089297 , HL-084946 and Fondation Leducq (Dr. Kass), HL-093432 (Drs. Takimoto and Kass), and T32-HL-07227 (Drs. Zhang and Barth) and a fellowship grant to Dr. Zhang from the American Heart Association . All authors have reported that they have no relationships to disclose.
PY - 2010/12/7
Y1 - 2010/12/7
N2 - Objectives We tested the hypothesis that bi-directional, gene-targeted regulation of cardiomyocyte cyclic guanosine monophosphateselective 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 monophosphatePKG regulatory pathways
AB - Objectives We tested the hypothesis that bi-directional, gene-targeted regulation of cardiomyocyte cyclic guanosine monophosphateselective 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 monophosphatePKG regulatory pathways
KW - Cyclic GMP
KW - Heart failure
KW - Phosphodiesterase-5
KW - Pressure overload
KW - Protein kinase G
KW - Transgenic mouse models
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U2 - 10.1016/j.jacc.2010.08.612
DO - 10.1016/j.jacc.2010.08.612
M3 - Article
C2 - 20970280
AN - SCOPUS:78649715496
SN - 0735-1097
VL - 56
SP - 2021
EP - 2030
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 24
ER -