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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Enhancement Award (SC1)
Project #
1SC1HL118669-01A1
Application #
8337107
Study Section
Special Emphasis Panel (ZGM1-MBRS-Y (SC))
Program Officer
Wong, Renee P
Project Start
2012-08-22
Project End
2017-05-31
Budget Start
2012-08-22
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$253,400
Indirect Cost
$78,400
Name
University of Puerto Rico Med Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
Javadov, Sabzali; Jang, Sehwan; Parodi-Rullán, Rebecca et al. (2017) Mitochondrial permeability transition in cardiac ischemia-reperfusion: whether cyclophilin D is a viable target for cardioprotection? Cell Mol Life Sci 74:2795-2813
Parodi-Rullán, Rebecca M; Chapa-Dubocq, Xavier; Rullán, Pedro J et al. (2017) High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated with Mitochondrial Abnormalities. Front Pharmacol 8:275
Kuznetsov, Andrey V; Javadov, Sabzali; Saks, Valdur et al. (2017) Synchronism in mitochondrial ROS flashes, membrane depolarization and calcium sparks in human carcinoma cells. Biochim Biophys Acta 1858:418-431
Jang, Sehwan; Javadov, Sabzali (2017) Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria. Arch Biochem Biophys 630:1-8
Huang, Yan; Powers, Corey; Moore, Victoria et al. (2017) The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome. Orphanet J Rare Dis 12:49
Barreto-Torres, Giselle; Javadov, Sabzali (2016) Possible Role of Interaction between PPAR? and Cyclophilin D in Cardioprotection of AMPK against In Vivo Ischemia-Reperfusion in Rats. PPAR Res 2016:9282087
Javadov, Sabzali; Jang, Sehwan; Rodriguez-Reyes, Natividad et al. (2015) Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats. Oncotarget 6:39469-81
Javadov, Sabzali (2015) The calcium-ROS-pH triangle and mitochondrial permeability transition: challenges to mimic cardiac ischemia-reperfusion. Front Physiol 6:83
Barreto-Torres, Giselle; Hernandez, Jessica Soto; Jang, Sehwan et al. (2015) The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPAR?-cyclophilin D interaction in cardiomyocytes. Am J Physiol Heart Circ Physiol 308:H749-58
Kuznetsov, Andrey V; Javadov, Sabzali; Sickinger, Stephan et al. (2015) H9c2 and HL-1 cells demonstrate distinct features of energy metabolism, mitochondrial function and sensitivity to hypoxia-reoxygenation. Biochim Biophys Acta 1853:276-84

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