Diabetic patients not only have increased vascular injury that causes higher morbidity of ischemic heart disease (IHD), but also have larger infarct size, severe heart failure, and higher mortality following a comparable degree of initial ischemic insult. Recent clinical and experimental results have demonstrated that adiponectin (APN) is a novel metabolic regulatory, vasculoprotective and cardioprotective molecule whose reduction found in diabetic patients contribute not only to increased morbidity of IHD, but also to increased MI/R injury in these individuals. Substantial evidence exists that AMP activated protein kinase (AMPK) plays an essential role in APN's metabolic and vasculoprotective effects. However, our preliminary experiments demonstrated that APN's cardioprotective effect in the ischemic heart is largely AMPK-independent but critically depends on adiponectin receptor-1/caveolin-3 interaction. The central hypothesis to be tested in this grant application is that novel adiponectin receptor-1/Caveolin-3 interaction mediated, AMPK-independent signaling pathway(s) initiated by specific APN isoform(s) with specific receptor activation may play a critical role in APN's cardioprotective effects against MI/R injury.
Three specific aims will be addressed.
Specific Aim 1 will utilize knockout mice and siRNA silencing technique to determine whether different forms of APN may preferentially bind to different type of receptors and protect cardiomyocytes against MI/R injury with different involvement of AMPK signaling system.
Specific Aim 2 will combine traditional pharmacologic and modern genetic approaches and attempt to identify the intracellular signaling mechanisms by which APN exerts its anti-oxidative, anti-nitrative, and cardioprotective actions in MI/R hearts.
Specific Aim 3 will identify novel cardioprotective targets for diabetic individuals with impaired APN-Caveolin signaling. The novel data resulting from the studies proposed in this application are not only scientifically significant because it will help us to understand the biological significance of ANP assembling and disassembling (presence of different isoforms) and how each isoform exerts its cardioprotective effect, but also clinically significant because it may identify optimal interventions for therapeutical needs under different pathologic conditions.

Public Health Relevance

The current grant application attempt to determine how adiponectin (APN), a protein made by fat cell, protect cardiomyocytes. The novel data resulting from the studies proposed in this application is not only scientifically significant because it will contribute to understanding the biological significance of APN assembling and disassembling, its different isoforms, and how each APN isoform exerts its cardioprotective effect, but is also clinically significant because it will identify novel targets for therapeutic application in different pathologic conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096686-03
Application #
8265655
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$383,625
Indirect Cost
$136,125
Name
Thomas Jefferson University
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
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
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 :
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
Wang, Yajing; Wang, Xiaoliang; Jasmin, Jean-Francois et al. (2012) Essential role of caveolin-3 in adiponectin signalsome formation and adiponectin cardioprotection. Arterioscler Thromb Vasc Biol 32:934-42
Zheng, Qijun; Yuan, Yuexing; Yi, Wei et al. (2011) C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol 31:2616-23
Lau, Wayne Bond; Tao, Ling; Wang, Yajing et al. (2011) Systemic adiponectin malfunction as a risk factor for cardiovascular disease. Antioxid Redox Signal 15:1863-73

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