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

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

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9 Scopus citations

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.

Original language	English
Pages (from-to)	17-28
Number of pages	12
Journal	FEBS Letters
Volume	596
Issue number	1
DOIs	https://doi.org/10.1002/1873-3468.14228
State	Published - Jan 2022
Externally published	Yes

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Zhu, G., Ueda, K., Hashimoto, M., Zhang, M., Sasaki, M., Kariya, T., Sasaki, H., Kaludercic, N., Lee, D. I., Bedja, D., Gabrielson, M., Yuan, Y., Paolocci, N., Blanton, R. M., Karas, R. H., Mendelsohn, M. E., O’Rourke, B., Kass, D. A., & Takimoto, E. (2022). The mitochondrial regulator PGC1α is induced by cGMP–PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure. FEBS Letters, 596(1), 17-28. https://doi.org/10.1002/1873-3468.14228

@article{0fae99ec11ae41869f2497a73afa2b8a,

title = "The mitochondrial regulator PGC1α is induced by cGMP–PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure",

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.",

author = "Guangshuo Zhu and Kazutaka Ueda and Masaki Hashimoto and Manling Zhang and Masayuki Sasaki and Taro Kariya and Hideyuki Sasaki and Nina Kaludercic and Lee, {Dong ik} and Djahida Bedja and Matthew Gabrielson and Yuan Yuan and Nazareno Paolocci and Blanton, {Robert M.} and Karas, {Richard H.} and Mendelsohn, {Michael E.} and Brian O{\textquoteright}Rourke and Kass, {David A.} and Eiki Takimoto",

note = "Publisher Copyright: {\textcopyright} 2021 Federation of European Biochemical Societies",

year = "2022",

month = jan,

doi = "10.1002/1873-3468.14228",

language = "English",

volume = "596",

pages = "17--28",

journal = "FEBS Letters",

issn = "0014-5793",

publisher = "Wiley-Blackwell",

number = "1",

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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 & Takimoto, E 2022, 'The mitochondrial regulator PGC1α is induced by cGMP–PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure', FEBS Letters, vol. 596, no. 1, pp. 17-28. https://doi.org/10.1002/1873-3468.14228

TY - JOUR

T1 - The mitochondrial regulator PGC1α is induced by cGMP–PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure

AU - Zhu, Guangshuo

AU - Ueda, Kazutaka

AU - Hashimoto, Masaki

AU - Zhang, Manling

AU - Sasaki, Masayuki

AU - Kariya, Taro

AU - Sasaki, Hideyuki

AU - Kaludercic, Nina

AU - Lee, Dong ik

AU - Bedja, Djahida

AU - Gabrielson, Matthew

AU - Yuan, Yuan

AU - Paolocci, Nazareno

AU - Blanton, Robert M.

AU - Karas, Richard H.

AU - Mendelsohn, Michael E.

AU - O’Rourke, Brian

AU - Kass, David A.

AU - Takimoto, Eiki

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

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U2 - 10.1002/1873-3468.14228

DO - 10.1002/1873-3468.14228

M3 - Article

C2 - 34778969

AN - SCOPUS:85119436598

SN - 0014-5793

VL - 596

SP - 17

EP - 28

JO - FEBS Letters

JF - FEBS Letters

IS - 1

ER -

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

Abstract

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