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Here, we investigated the role of the mitochondrial regulator peroxisome proliferator\u2010activated receptor \u03b3 co\u2010activator\u20101\u03b1 (PGC1\u03b1) in the PDE5i\u2010conferred cardioprotection, utilizing PGC1\u03b1 null mice. In PGC1\u03b1<jats:sup>+\/+<\/jats:sup> hearts exposed to 7\u2009weeks 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 PGC1\u03b1 mRNA in the myocardium. By contrast, PDE5i\u2010elicited benefits were abrogated in PGC1\u03b1<jats:sup>\u2212\/\u2212<\/jats:sup> hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1\u03b1, while inhibition of the transcription factor CREB abrogated the PGC1\u03b1 induction. Together, these results suggest that the PKG\u2013PGC1\u03b1 axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.<\/jats:p>","DOI":"10.1002\/1873-3468.14228","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T05:09:22Z","timestamp":1636952962000},"page":"17-28","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The mitochondrial regulator PGC1\u03b1 is induced by cGMP\u2013PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure"],"prefix":"10.1002","volume":"596","author":[{"given":"Guangshuo","family":"Zhu","sequence":"first","affiliation":[{"name":"Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of 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