Cardiovascular disease increases markedly with advancing age in our Veteran population. In aging, myocardial injury is increased during ischemia (ISC)-reperfusion (REP) and leads to heart failure. Mitochondrial-driven injury during ISC-REP in aged hearts is mediated by the electron transport chain (ETC) due to increased production of reactive oxygen species (ROS) and damage to the mitochondrial phospholipid cardiolipin (CL). Most therapeutic strategies that effectively decrease cardiac injury in younger hearts fail in aged hearts. In contrast, we found that a transient, reversible inhibition of ETC complex I during early REP decreased injury in the aged heart. The key mechanism and target of protection at the cellular level that mediates ETC-driven protection remains a critical unanswered question. In addition to mitochondria (MITO) damage, endoplasmic reticulum (ER) stress contributes to cardiac injury. MITO and ER are juxtaposed through shared structures of mitochondria-associated membranes (MAM). MAM contribute a critical role in calcium regulation and lipid metabolism between MITO and ER. Disruption of MAM integrity likely mediates pathologic ?cross talk? between ER and MITO and increases cardiac injury. We found that CL exists in MAM and the ER with a composition distinct from MITO. Our previous work showed that CL content in MITO is decreased and exhibits an increase in oxidized CL content following ISC-REP in the aged heart. ER is a key site for the remodeling/repair of damaged CL. We hypothesize that CL is a key mediator of the ?cross talk? between MITO and ER via the MAM, and that trafficking of damaged CL to ER via the MAM is a mediator of MAM disruption in the aged heart during ISC-REP. Age-induced ETC defects increase ROS production. MITO ROS can damage MAM and activate ER stress responses. We found that aging augments cardiac ER stress. MAM are uniquely positioned to sustain damage from both MITO and ER. The increased ROS from aged heart MITO may damage CL in the MAM and activate ER stress. We will evaluate the role of primary MITO dysfunction at baseline and then following ISC and early REP to MAM damage and CL modification in Aim 1. The role of ETC inhibition to protect MAM during ISC-REP is studied (Aim 1). The response of MAM and ER to ISC-REP in the aged heart is unknown (Aim 2). Acute, transient complex I blockade with a reversible inhibitor decreases injury in aged hearts. We found that metformin inhibits complex I in a dose-dependent manner, especially in ISC-damaged heart MITO. Next, we showed that metformin treatment only at REP in doses that inhibit complex I decreases infarct size in vivo following 24 hrs. REP. We hypothesize that modulation of complex I at REP in aged hearts will attenuate damage to the MAM with a subsequent decrease in ER stress that, in turn, minimizes the generation of dysfunctional MITO and cardiac injury. The partial inhibition of complex I is studied as a new upstream therapeutic intervention to attenuate cardiac injury and minimize post-infarction heart failure development in aged hearts (Aim 3).

Public Health Relevance

Elderly Veterans have a high incidence of coronary artery disease. During a heart attack, elderly patients unfortunately sustain greater heart damage compared to younger patients. This disparity persists despite successful treatment of the heart attack with rapid restoration of blood flow to the heart. Our research found that the aged heart is intrinsically more susceptible to injury during a heart attack. This increased risk is due to dysfunctional mitochondria, the ?powerhouses? of the heart cell. During a heart attack, these deranged mitochondria lead to heart cell death, in part by injuring other cell organelles, serving to amplify cell injury. This proposal builds upon our previous work to directly manipulate metabolism in mitochondria in order to consolidate protection of the vulnerable aged heart, decrease heart damage and improve heart attack outcomes in high-risk older Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001355-06
Application #
9378377
Study Section
Cardiovascular Studies A (CARA)
Project Start
2012-04-01
Project End
2020-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Veterans Administration Hospital
Department
Type
DUNS #
146678115
City
Richmond
State
VA
Country
United States
Zip Code
23249
Chen, Qun; Lesnefsky, Edward J (2018) A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1. Cardiovasc Res 114:771-772
Chen, Qun; Aluri, Hema; Lesnefsky, Edward J (2018) Cardiac protection by moving the mitochondria? Int J Cardiol 271:256-257
He, Liu; Jiang, Yuqi; Liu, Kai et al. (2018) Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer's Disease. J Med Chem 61:777-790
Chen, Qun; Younus, Masood; Thompson, Jeremy et al. (2018) Intermediary metabolism and fatty acid oxidation: novel targets of electron transport chain-driven injury during ischemia and reperfusion. Am J Physiol Heart Circ Physiol 314:H787-H795
Hoppel, Charles L; Lesnefsky, Edward J; Chen, Qun et al. (2017) Mitochondrial Dysfunction in Cardiovascular Aging. Adv Exp Med Biol 982:451-464
Lesnefsky, Edward J; Chen, Qun; Tandler, Bernard et al. (2017) Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies. Annu Rev Pharmacol Toxicol 57:535-565
Chen, Qun; Thompson, Jeremy; Hu, Ying et al. (2017) Metformin attenuates ER stress-induced mitochondrial dysfunction. Transl Res 190:40-50
Chen, Qun; Lesnefsky, Edward J (2017) A New Strategy to Treat Mitochondrial Disease Without Improvement of Mitochondrial Function? EBioMedicine 18:19-20
Ma, Yibao; Min, Hae-Ki; Oh, Unsong et al. (2017) The lignan manassantin is a potent and specific inhibitor of mitochondrial complex I and bioenergetic activity in mammals. J Biol Chem 292:20989-20997
Lesnefsky, Edward J; Chen, Qun; Hoppel, Charles L (2016) Mitochondrial Metabolism in Aging Heart. Circ Res 118:1593-611

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