Abstract

Nitro-compounds (e.g., nitroglycerin), as exogenous NO donors, have been used to treat MI for over one hundred years. The benefits of NO- treatment in reperfusion, however, have recently been challenged. Biochemical evidence reveals that ONOO-, the reaction product of NO with O2, is a highly reactive moiety that causes tissue damage comparable to that caused by OH Although these in vitra studies support a role for ONOO- in myocardial reperfusion injury, extension of these observations to relevant whole organs or to in viva models is lacking. More importantly, recent studies suggest that the effects of ONOO- are critically dependent on the microenvironment in which this oxidant is produced. The long-term goal of this project is to enhance the understanding of ONOO- in reperfusion injury.
In specific aim number 1, chemically-synthesized ONOO- will be continually infused into the left atrium of rabbits at various doses and intervals during coronary occlusion or reperfusion. The effects of this exogenous ONOO- on infarct size, cardiac function, and PMN accumulation will be evaluated in a clinically relevant in vivo model.
In specific aim number 2, endogenous ONOO- will be inhibited by administration of superoxide, nitric oxide, or ONOO- scavenger. The role of endogenously formed ONOO- in reperfusion will be evaluated and different strategies aimed at decreasing ONOO- concentration to a level that protects against reperfusion injury will be studied- In specific aim number3, the mechanisms by which ONOO- influences PMN-EC interactions will be determined in isolated rabbit neutrophils and cultured rabbit microvascular endothelial cells. The proposed studies are clinically relevant because the results may alter future treatment of cardiac ischemia. The studies outlined in this proposal are fundamental to understanding the role of NO in ischemia-reperfusion injury, and are prerequisite to clinical trials designed to decrease reperfusion injury through the manipulation of NO production.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063828-02
Application #
6537715
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Massicot-Fisher, Judith
Project Start
2001-07-10
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$273,610
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Wang, Yajing; Wang, Xiaoliang; Lau, Wayne Bond et al. (2014) Adiponectin inhibits tumor necrosis factor-?-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation. Circ Res 114:792-805
Zhao, Jianli; Wang, Feng; Zhang, Yanqing et al. (2013) Sevoflurane preconditioning attenuates myocardial ischemia/reperfusion injury via caveolin-3-dependent cyclooxygenase-2 inhibition. Circulation 128:S121-9
Sun, Yang; Yi, Wei; Yuan, Yuexing et al. (2013) C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation. Circulation 128:S113-20
Pu, Jun; Yuan, Ancai; Shan, Peiren et al. (2013) Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. Eur Heart J 34:1834-45
Zhang, Yanqing; Zhao, Jianli; Lau, Wayne Bond et al. (2013) Tumor necrosis factor-? and lymphotoxin-? mediate myocardial ischemic injury via TNF receptor 1, but are cardioprotective when activating TNF receptor 2. PLoS One 8:e60227
Lau, Wayne Bond; Zhang, Yanqing; Zhao, Jianli et al. (2013) Lymphotoxin-ýý is a novel adiponectin expression suppressor following myocardial ischemia/reperfusion. Am J Physiol Endocrinol Metab 304:E661-7
Su, Hui; Yuan, Yuexing; Wang, Xiao-Ming et al. (2013) Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNF?-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice. Basic Res Cardiol 108:315
Zhang, Yanqing; Wang, Xiao-Liang; Zhao, Jianli et al. (2013) Adiponectin inhibits oxidative/nitrative stress during myocardial ischemia and reperfusion via PKA signaling. Am J Physiol Endocrinol Metab 305:E1436-43
Wang, Yajing; Zhao, Jianli; Zhang, Yanqing et al. (2013) Differential regulation of TNF receptor 1 and receptor 2 in adiponectin expression following myocardial ischemia. Int J Cardiol :
Wang, Yajing; Wang, Xiaoliang; Jasmin, Jean-François et al. (2012) Essential role of caveolin-3 in adiponectin signalsome formation and adiponectin cardioprotection. Arterioscler Thromb Vasc Biol 32:934-42

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