The mitochondrial regulator PGC1α is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure

Guangshuo Zhu; Kazutaka Ueda; Masaki Hashimoto; Manling Zhang; Masayuki Sasaki; Taro Kariya; Hideyuki Sasaki; Nina Kaludercic; Dong-Ik Lee; Djahida Bedja; Matthew Gabrielson; Yuan Yuan; Nazareno Paolocci; Robert M Blanton; Richard H Karas; Michael E Mendelsohn; Brian O'Rourke; David A Kass; Eiki Takimoto

doi:10.1002/1873-3468.14228

The mitochondrial regulator PGC1α is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure

FEBS Lett. 2022 Jan;596(1):17-28. doi: 10.1002/1873-3468.14228. Epub 2021 Nov 19.

Authors

Guangshuo Zhu¹, Kazutaka Ueda^{2

3}, Masaki Hashimoto², Manling Zhang¹, Masayuki Sasaki¹, Taro Kariya¹, Hideyuki Sasaki¹, Nina Kaludercic¹, Dong-Ik Lee¹, Djahida Bedja¹, Matthew Gabrielson¹, Yuan Yuan¹, Nazareno Paolocci¹, Robert M Blanton³, Richard H Karas³, Michael E Mendelsohn^{3

4}, Brian O'Rourke¹, David A Kass¹, Eiki Takimoto^{1

2}

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
³ Molecular Cardiology Research Institute and Division of Cardiology, Tufts Medical Center, Boston, MA, USA.
⁴ Cardurion Pharmaceuticals, Boston, MA, USA.

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.

Keywords: PGC1α; cyclic guanosine monophosphate; heart failure; mitochondria.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cyclic AMP Response Element-Binding Protein / genetics
Cyclic AMP Response Element-Binding Protein / metabolism
Cyclic GMP* / metabolism
Cyclic GMP-Dependent Protein Kinases* / genetics
Cyclic GMP-Dependent Protein Kinases* / metabolism
Heart Failure* / drug therapy
Heart Failure* / genetics
Heart Failure* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondria, Heart / drug effects
Mitochondria, Heart / metabolism
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
Phosphodiesterase 5 Inhibitors* / pharmacology
Signal Transduction* / drug effects
Sildenafil Citrate* / pharmacology

Substances

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phosphodiesterase 5 Inhibitors
Cyclic GMP-Dependent Protein Kinases
Ppargc1a protein, mouse
Cyclic GMP
Sildenafil Citrate
Cyclic AMP Response Element-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding