The overall goal is to elucidate the molecular and physiological mechanisms in the heart that promote cardioprotection against myocardial ischemia and ischemia/reperfusion (I/R) injury in the elderly. With aging, the ability of the myocardium to tolerate ischemic stress becomes compromised. Consequently, there is more morbidity and mortality in patients that are over 70 years of age receiving current interventions for myocardial infarction. Yet the mechanisms responsible for this age-related impairment in the adaptive response to I/R remains incompletely understood. Therefore, understanding the alteration of these mechanisms within the aging heart is fundamental for improving therapeutic strategies targeted against such cardiovascular pathologies. Our group and others have provided extensive evidence suggesting that activation of the AMP- activated protein kinase (AMPK) signaling pathway is highly advantageous to the heart. Moreover, we have recently demonstrated that during myocardial ischemia, AMPK activation is significantly impaired in the aged heart and that this is directly associated with increased myocardial infarction and cardiac dysfunction. However, how AMPK is activated during myocardial ischemia in addition to the endogenous mechanisms explaining the differences observed in impaired AMPK activation between young and aged hearts remains largely elusive. Recently, a novel group of proteins that lack kinase activity, known as the sestrins, particularly Sestrin2, have been demonstrated to increase the activation of AMPK in vitro and in vivo. Sestrin2 also limits cell death against hypoxic insults, limits oxidative stress, and increases the autophagic flux, all of which are important in age-related cardiac dysfunction. Accordingly, we hypothesize that Sestrin2 may be an integral part of the stress response that occurs during myocardial I/R and that its cooperation with the AMPK signaling pathway is altered with cardiac senescence. This hypothesis will be tested with two aims. First, we aim to define sestrin2 as a critical component of the adaptive response during I/R injury. Second, we aim to characterize how Sestrin2 is involved in the impaired AMPK signaling pathway during I/R in the aged heart. The proposed research takes an interdisciplinary approach encompassing physiologically relevant in vivo and ex vivo models of aging and I/R injury. In this manner, the proposed research will highlight new therapeutic targets and further our understanding about how specific stress-activated cardioprotective pathways are impaired with aging.

Public Health Relevance

Ischemic heart disease, which affects approximately one million Americans each year, is most often caused by ischemic insults leading to myocardial damage. This grant seeks to understand the ways in which impaired cardioprotective signaling leads to a higher incidence of ischemic heart disease in the aged population, and has the potential to discover new therapeutic strategies to limit myocardial dysfunction in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Kohanski, Ronald A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Buffalo
Schools of Medicine
United States
Zip Code
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
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
Quan, Nanhu; Wang, Lin; Chen, Xu et al. (2018) Sestrin2 prevents age-related intolerance to post myocardial infarction via AMPK/PGC-1? pathway. J Mol Cell Cardiol 115:170-178
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
Yang, Hui; Sun, Wanqing; Quan, Nanhu et al. (2016) Cardioprotective actions of Notch1 against myocardial infarction via LKB1-dependent AMPK signaling pathway. Biochem Pharmacol 108:47-57
Sun, Wanqing; Quan, Nanhu; Wang, Lin et al. (2016) Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress. Toxicol Sci 151:193-203

Showing the most recent 10 out of 15 publications