Clinical studies report a higher incidence of ischemic heart disease and mortality after myocardial infarction, coronary angioplasty, or cardiac surgery in patients older than 60 years of age, which appear to be related to a decline in intrinsic myocardial resistance to injury. The mechanisms responsible for age-related ischemic intolerance are incompletely understood and the signaling pathways involved in regulating cellular responses to ischemia/reperfusion remain largely unknown. We recently reported that an aging-associated reduction in AMP-activated protein kinase (AMPK) signaling is an important contributing factor leading to increased sensitivity to ischemic stress via modulation of the glucose transporter (GLUT4) translocation. Intriguingly, Sirtuin 1 (SIRT1), a longevity protein, is emerging as a potential AMPK downstream target involved in heart disease. Therefore, it is hypothesized that the impaired AMPK-SIRT1 signaling cascade in the aged heart contributes to intolerance to ischemic insults in the elderly. We will test this hypothesis to investigate the importance of SIRT1 signaling in the susceptibility of the aged heart to ischemic insults.
Aim 1 : To characterize the SIRT1 activation in the aged heart during ischemia/reperfusion;
Aim 2 : To determine the role of SIRT1 in regulating cardiac function during ischemia-reperfusion stress;
Aim 3 : To evaluate the capability of a small-molecule AMPK or SIRT1 agonist to improve ischemia/reperfusion-induced adaptive response in the aged heart. In this manner, we will advance our understanding of the mechanisms behind aging-associated alterations in cardiac SIRT1 signaling pathways in response to ischemic stress. Furthermore, we propose a novel therapeutic strategy that might up-regulate cardiac SIRT1 signaling and thus protect against ischemia- induced cardiac injury in this segment of population.

Public Health Relevance

We seek to understand the basis for increased susceptibility of the aged myocardium to ischemic injury via investigating signaling mechanisms underlying altered adaptive responses to cardiac ischemic stress with aging. The study also explores whether a pharmacological approach targeting a novel signaling pathway in addition to dietary changes could improve the adaptive signaling mechanisms in the aged heart. Findings from the study could lead to novel therapeutic strategies aimed at limiting ischemic cardiac damage in aging populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG049835-01
Application #
8863717
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Velazquez, Jose M
Project Start
2015-04-15
Project End
2020-03-31
Budget Start
2015-04-15
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$315,433
Indirect Cost
$99,023
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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Cates, Courtney; Rousselle, Thomas; Wang, Jinli et al. (2018) Activated protein C protects against pressure overload-induced hypertrophy through AMPK signaling. Biochem Biophys Res Commun 495:2584-2594
Wang, Lin; Quan, Nanhu; Sun, Wanqing et al. (2018) Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury. Cardiovasc Res 114:805-821
Li, Xuan; Liu, Jia; Hu, Haiyan et al. (2018) Dichloroacetate ameliorates cardiac dysfunction caused by ischemic insults through AMPK signal pathway- not only shifts metabolism. Toxicol Sci :
Chen, Xu; Li, Xuan; Zhang, Wenyan et al. (2018) Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-?B pathway. Metabolism 83:256-270
Feng, Ruiqi; Liu, Jia; Wang, Zhenhua et al. (2017) The structure-activity relationship of ginsenosides on hypoxia-reoxygenation induced apoptosis of cardiomyocytes. Biochem Biophys Res Commun 494:556-568
Zhang, Celia; Sun, Wei; Li, Ji et al. (2017) Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea. Neuroscience 361:179-191
Quan, Nanhu; Sun, Wanqing; Wang, Lin et al. (2017) Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J 31:4153-4167
Zhang, Jie; Zhao, Peng; Quan, Nanhu et al. (2017) The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy. Biochem Biophys Res Commun 492:520-527
Wang, Jinli; Ma, Yina; Sachs, Frederick et al. (2016) GsMTx4-D is a cardioprotectant against myocardial infarction during ischemia and reperfusion. J Mol Cell Cardiol 98:83-94

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