Journal
FEBS LETTERS
Volume 596, Issue 1, Pages 17-28Publisher
WILEY
DOI: 10.1002/1873-3468.14228
Keywords
cyclic guanosine monophosphate; heart failure; mitochondria; PGC1 alpha
Funding
- NIH [HL-093432, HL-131831, HL-089297]
- American Heart Association [11GRNT7700071]
- Muscular Dystrophy Association [186454]
- Foundation Leducq
- Abraham and Virginia Weiss Endowment
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This study found that PDE5i improves heart failure by activating the PKG-PGC1 alpha axis, which enhances mitochondrial respiration and upregulates PGC1 alpha mRNA. However, the cardioprotective effects of PDE5i were abolished in hearts lacking the PGC1 alpha gene.
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 gamma co-activator-1 alpha (PGC1 alpha) in the PDE5i-conferred cardioprotection, utilizing PGC1 alpha null mice. In PGC1 alpha(+/+) 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 PGC1 alpha mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1 alpha(-/-) hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1 alpha, while inhibition of the transcription factor CREB abrogated the PGC1 alpha induction. Together, these results suggest that the PKG-PGC1 alpha axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.
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