Cardiac remodeling following myocardial infarction is the initial myocardial hypertrophic response which follows myocardial injury and the eventual evolution to heart failure. Attenuation of the early adaptive hypertrophy can be translated into attenuation of heart failure response such that understanding the molecular and cellular mechanisms underlying progression of cardiac remodeling to heart failure is of crucial importance. Mitochondrial dysfunction is central to the loss of contractile function during ventricular remodeling/heart failure that are thought to be induced as a result of inactivation of cell signaling molecules, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha (PGC-1alpha). Mitochondrial permeability transition pore (MPTP) opening has been shown to be an end-effector for cell death that is associated with increased mitochondrial fragmentation due to alterations in the balance between fission and fusion of mitochondria. In this proposal, we hypothesize that the alterations in the AMPK/PGC-1alpha cascade trigger MPTP opening leading to cardiac dysfunction in post-infarction cardiac remodeling;modulation of the MPTP occurs through a direct interaction of AMPK/PGC-1alpha with the pore complex and/or indirectly, through AMPK-induced acetylation of cyclophilin D. To test our hypothesis we will study the intact heart, cultured cardiomyocytes and isolated mitochondria using an in vivo rat model of post-infarction remodeling and an in vitro model of rat cardiomyocyte hypertrophy. We have extensive experience with the proposed animal and cell models, and the necessary techniques to study mitochondrial function in cardiac diseases, and develop new pharmacological and conditional strategies for cardioprotection.
The specific aims of this proposal are to: (1) Examine whether progression of post-infarction remodeling to heart failure is associated with increased MPTP opening and mitochondrial fragmentation;(2) Determine whether MPTP formation is regulated by the AMPK/PPARalpha pathway in cardiac remodeling;(3) Define whether inhibition of MPTP has long-term protective effects during post-infarction remodeling. The proposed studies will identify the specific mitochondrial adaptations and alterations, and help develop new therapeutic strategies for treatment of post-myocardial infarction heart failure.

Public Health Relevance

The proposed studies are aimed at elucidating the mechanisms involved in mitochondria-mediated cardiac dysfunction with progression of post-infarction remodeling to heart failure. Particularly, the relationship between mitochondrial permeability transition pore (MPTP) opening/mitochondrial fragmentation and cardiac dysfunction will be investigated in an in vivo model of post-infarction cardiac remodeling and an in vitro model of cardiomyocyte hypertrophy. Since the mitochondria play a critical role in cell death through apoptosis and necrosis, prevention or reversal of MPTP opening is crucial to protect the heart against cardiac diseases. Therefore, the cardioprotective effects of the specific inhibitor for the main MPTP regulatory protein cyclophilin D, sanglifehrin A will be used in the present study to guard the heart against ventricular remodeling/heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1-MBRS-Y (SC))
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Wong, Renee P
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University of Puerto Rico Med Sciences
Schools of Medicine
San Juan
United States
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Javadov, Sabzali; Jang, Sehwan; Agostini, Bryan (2014) Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives. Pharmacol Ther 144:202-25
Nuñez, Rebeca E; Castro, Miriam; Javadov, Sabzali et al. (2014) Angiotensin II and ischemic preconditioning synergize to improve mitochondrial function while showing additive effects on ventricular postischemic recovery. J Cardiovasc Pharmacol 64:172-9
Hernández, Jessica Soto; Barreto-Torres, Giselle; Kuznetsov, Andrey V et al. (2014) Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria. J Cell Mol Med 18:709-20
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Javadov, Sabzali (2014) Letter to the editor: "cyclosporin A in left ventricular remodeling after myocardial infarction". Am J Physiol Heart Circ Physiol 306:H777