کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2572789 1129328 2014 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond
چکیده انگلیسی


• The presence of PDE5 in murine CMs has been questioned by recent studies.
• Clinical trials testing PDE5 inhibition for different cardiac disease settings has failed.
• Effects of the PDE5 inhibitor sildenafil on non-myocyte cardiac cells need to be better evaluated.
• Favorable effects of cGMP/cGKI in the heart are under the control of a large set of PDEs.
• Antifibrotic effects of PDE5 inhibition and elevated cGMP likely stem from myofibroblasts/fibroblasts and require cGKI.

cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia–reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP–cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re-evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 35, Issue 8, August 2014, Pages 404–413
نویسندگان
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