1. The mitochondrial regulator PGC1α is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure.
- Author
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Zhu G, Ueda K, Hashimoto M, Zhang M, Sasaki M, Kariya T, Sasaki H, Kaludercic N, Lee DI, Bedja D, Gabrielson M, Yuan Y, Paolocci N, Blanton RM, Karas RH, Mendelsohn ME, O'Rourke B, Kass DA, and Takimoto E
- Subjects
- Animals, Mice, Myocytes, Cardiac metabolism, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Mitochondria metabolism, Mitochondria drug effects, Cyclic AMP Response Element-Binding Protein metabolism, Cyclic AMP Response Element-Binding Protein genetics, Mitochondria, Heart metabolism, Mitochondria, Heart drug effects, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Phosphodiesterase 5 Inhibitors pharmacology, Heart Failure metabolism, Heart Failure drug therapy, Heart Failure genetics, Cyclic GMP-Dependent Protein Kinases metabolism, Cyclic GMP-Dependent Protein Kinases genetics, Cyclic GMP metabolism, Signal Transduction drug effects, Sildenafil Citrate pharmacology
- Abstract
Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α
+/+ hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α-/- hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG-PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure., (© 2021 Federation of European Biochemical Societies.)- Published
- 2022
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