Myocardial infarction (MI) remains a major cause of death in the United States. Ischemic preconditioning is one of the most beneficial interventions to protect the heart from MI, though a precise target and therefore a specific therapeutic approach to produce preconditioning and prevent MI are not known. To address these gaps in knowledge, our prior grant application hypothesized that IPC-mediated modulation of caveolin, a scaffolding protein found in lipid raft membrane microdomains (caveolae), is critical for coupling the sarcolemma to mitochondria and the regulation of mitochondrial function and generation of reactive oxygen species (ROS) in the setting of ischemia-reperfusion (I/R) injury. Caveolin can protect the heart from ischemic damage: IPC-induced transfer of caveolin to mitochondria leads to stabilization of mitochondrial structure and function. We find that this mechanism is a general one: it occurs in C. elegans and cancer. Specific targeting of caveolin to mitochondria replicates this IPC-like effect but mice that lack cardiac caveolin cannot be preconditioned. Such data strongly implicate the importance of caveolin in plasma membrane-mitochondria communication and in IPC. However, the precise mechanisms by which caveolin stabilizes the ischemic myocardium are not known. Cellular membranes are dynamic entities that create barriers between two environments by their composition of proteins and lipids. In addition to the plasma membrane, the function of intracellular structures such as mitochondria, endoplasmic reticulum, nucleus and Golgi complex, derives in part from their membranes. I/R injury damages sarcolemmal membranes. Key benefits of IPC include its stabilization of sarcolemmal ultrastructure, preservation of mitochondrial membrane potential and reduced generation of ROS. Our finding that IPC can transfer plasma membrane caveolin to mitochondria suggests that caveolin regulates membrane function in these two compartments, and its increase in expression in mitochondria may be a critical mechanism for cellular adaptation to stress. We hypothesize that: The accumulation of caveolin in sarcolemmal and mitochondrial membranes following ischemic stress and in response to IPC increases membrane repair to limit injury and stabilize cellular function. Thus, enhancing caveolin expression and interaction with reparative processes will provide a therapeutic approach to treat ischemia-reperfusion injury. The following specific aims will test this hypothesis:
Aim 1 : Define the role of caveolin in sarcolemmal membrane repair during I/R injury.
Aim 2 : Define the role of caveolin in mitochondrial membrane dynamics and function during I/R injury.

Public Health Relevance

Injury form a heart attack is lethal and results in death. Certain proteins found in the heart control the degree of injury and may be involved in repairing injury. It is the goal of this study to discover key proteins involved in protection against a hear attack injury so that drugs can be appropriately designed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091071-07
Application #
9249088
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2007-12-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411
Busija, Anna R; Patel, Hemal H; Insel, Paul A (2017) Caveolins and cavins in the trafficking, maturation, and degradation of caveolae: implications for cell physiology. Am J Physiol Cell Physiol 312:C459-C477
Kassan, Adam; Egawa, Junji; Zhang, Zheng et al. (2017) Caveolin-1 regulation of disrupted-in-schizophrenia-1 as a potential therapeutic target for schizophrenia. J Neurophysiol 117:436-444
Mandyam, Chitra D; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry 81:101-110

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