Ischemia/reperfusion causes endothelial dysfunction leading to impaired endothelium-dependent vascular relaxation in hearts. Postischemic endothelial dysfunction has been attributed to a decrease in nitric oxide (NO) formation and increase in superoxide production. This unbalanced NO decrease/superoxide increase are the key initiating events in the pathogenesis of myocardial reperfusion injury. But the molecular mechanism underlying NO decrease/superoxide increase in postischemic endothelial cells remains poorly understood. In cardiovascular system, NO is primarily produced by endothelial NO synthase (eNOS). Besides synthesizing NO, the applicant and others found that eNOS also produces superoxide and this process is triggered by low levels of tetrahydrobiopterin. Superoxide generated by uncoupled eNOS has been implicated in various diseases. But the role of eNOS-catalyzed superoxide in postischemic endothelial dysfunction has not been explored yet. The preliminary studies in this proposal show that tetrahydrobiopterin is depleted in postischemic hearts and this may change eNOS function from NO to superoxide synthesis. Elevated methylarginines and protein phosphorylation appear to further enhance eNOS to produce superoxide in postischemic hearts. Thus, it is hypothesized that the NO decrease/superoxide increase in dysfunctional endothelial cells in postischemic hearts is caused by a switch of eNOS function from NO to superoxide generation. To test this hypothesis, the following specific aims are proposed: 1) To determine whether a tetrahydrobiopterin depletion-mediated switch of eNOS function from NO to superoxide synthesis renders NO decrease/superoxide increase in postischemic hearts;2) To define the roles of endogenous methylarginines in regulating superoxide generation from eNOS in postischemic hearts;3) To determine the effect of protein phosphorylation on superoxide generation from eNOS in postischemic hearts. For each of these aims, measurements of NO and superoxide will be combined with molecular, cellular, and physiological approaches to characterize the roles of eNOS-derived superoxide in postischemic endothelial injury. Results from these studies will provide fundamental mechanistic information regarding how unbalanced NO decrease/superoxide increase occurs in postischemic endothelial cells. This information may lead to new approaches to treat endothelial dysfunction and improve postischemic cardiac function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086965-03
Application #
7626655
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2007-06-05
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$375,000
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Wang, Tingting; Luo, Suxin; Qin, Honghua et al. (2018) Hsp90 inhibition renders iNOS aggregation and the clearance of iNOS aggregates by proteasomes requires SPSB2. Free Radic Biol Med 117:90-98
Luo, Suxin; Lei, Han; Qin, Honghua et al. (2014) Molecular mechanisms of endothelial NO synthase uncoupling. Curr Pharm Des 20:3548-53
Zhang, Lijun; Liu, Qing; Yuan, Xiaomei et al. (2013) Requirement of heat shock protein 70 for inducible nitric oxide synthase induction. Cell Signal 25:1310-7
Wang, Tingting; Xia, Yong (2012) Inducible nitric oxide synthase aggresome formation is mediated by nitric oxide. Biochem Biophys Res Commun 426:386-9
Xiao, Zhihong; Wang, Tingting; Qin, Honghua et al. (2011) Endoplasmic reticulum Ca2+ release modulates endothelial nitric-oxide synthase via extracellular signal-regulated kinase (ERK) 1/2-mediated serine 635 phosphorylation. J Biol Chem 286:20100-8
Luo, Suxin; Wang, Tingting; Qin, Honghua et al. (2011) Obligatory role of heat shock protein 90 in iNOS induction. Am J Physiol Cell Physiol 301:C227-33
Ni, Li; Zhou, Changqing; Duan, Quanlu et al. (2011) ?-AR blockers suppresses ER stress in cardiac hypertrophy and heart failure. PLoS One 6:e27294
Xia, Yong (2009) How does Viagra protect the ischemic heart? Am J Physiol Heart Circ Physiol 296:H1209-10
Moens, An L; Leyton-Mange, Jordan S; Niu, Xiaolin et al. (2009) Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor. J Mol Cell Cardiol 47:576-85
Li, Xiaoxia; Wang, Peihua; Xu, Xizhen et al. (2009) Simvastatin increases the activity of endothelial nitric oxide synthase via enhancing phosphorylation. J Huazhong Univ Sci Technolog Med Sci 29:286-90

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