期刊
BASIC RESEARCH IN CARDIOLOGY
卷 106, 期 4, 页码 635-643出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-011-0167-y
关键词
Soluble guanylate cyclase; Ischemic preconditioning; Isolated heart; Contractility; Nitric oxide
资金
- American Heart Association
- Philips
- National Institute of Health [GM079360]
Nitric oxide (NO)-dependent soluble guanylate cyclase (sGC) activation is an important component of cardiac signal transduction pathways, including the cardioprotective signaling cascade induced by ischemic preconditioning (IPC). The sGC alpha subunit, which binds to the common sGC beta 1 subunit, exists in two different isoforms, sGC alpha 1 and sGC alpha 2, but their relative physiological roles remain unknown. In the present study, we studied Langendorff-perfused isolated hearts of genetically engineered mice lacking functional sGC alpha 1 (sGC alpha 1KO mice), which is the predominant isoform in the heart. Our results show that the loss of sGC alpha 1 has a positive inotropic and lusitropic effect on basal cardiac function, indicating an important role for sGC alpha 1 in regulating basal myocardial contractility. Surprisingly, IPC led to a similar 35-40% reduction in infarct size and concomitant protein kinase C epsilon (PKC epsilon) phosphorylation in both wild-type (WT) and sGC alpha 1KO hearts subjected to 40 min of global ischemia and reperfusion. Inhibition of the activation of all sGC isoforms by 1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 mu mol/L) completely abolished the protection by IPC in WT and sGC alpha 1KO hearts. NO-stimulated cGMP production was severely attenuated in sGC alpha 1KO hearts compared to WT hearts, indicating that the sGC alpha 2 isoform only produces minute amounts of cGMP after NO stimulation. Taken together, our results indicate that although sGC alpha 1 importantly regulates cardiac contractility, it is not required for cardioprotection by IPC. Instead, our results suggest that possibly only minimal sGC activity, which in sGC alpha 1KO hearts is provided by the sGC alpha 2 isoform, is sufficient to transduce the cardioprotective signal induced by IPC via phosphorylation of PKC epsilon.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据