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线粒体调节因子 PGC1α 受 cGMP-PKG 信号诱导，并介导磷酸二酯酶 5 抑制在心衰中的保护作用。

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

机构信息

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

出版信息

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

DOI:10.1002/1873-3468.14228
PMID:34778969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9199229/
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.

摘要

磷酸二酯酶 5 抑制剂（PDE5i）激活环鸟苷酸依赖性蛋白激酶（PKG）并改善心力衰竭；然而，其对心脏线粒体调节的影响尚未完全确定。在这里，我们利用过氧化物酶体增殖物激活受体γ共激活物 1α（PGC1α）缺失小鼠研究了线粒体调节剂 PGC1α 在 PDE5i 介导的心脏保护中的作用。在 PGC1α 心脏暴露于横主动脉缩窄 7 周的压力超负荷下，慢性给予 PDE5 抑制剂西地那非可改善心脏功能和重构，心肌线粒体呼吸得到改善，PGC1αmRNA 上调。相比之下，PDE5i 诱发的益处在 PGC1α 心脏中被消除。在培养的心肌细胞中，PKG 过表达诱导 PGC1α，而转录因子 CREB 的抑制消除了 PGC1α 的诱导。总之，这些结果表明 PKG-PGC1α 轴在 PDE5i 治疗心力衰竭的疗效中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/366db2506264/nihms-1810111-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/87d712a6f7ad/nihms-1810111-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/7c3662258659/nihms-1810111-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/c768f68ed963/nihms-1810111-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/366db2506264/nihms-1810111-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/87d712a6f7ad/nihms-1810111-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/7c3662258659/nihms-1810111-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/c768f68ed963/nihms-1810111-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea10/9199229/366db2506264/nihms-1810111-f0004.jpg

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