Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that affects an estimated 34% of the U.S. population and increases the risk of developing cardiovascular disease, including metabolic heart disease (MHD). MHD, which is characterized by left ventricular (LV) hypertrophy and impaired diastolic relaxation, culminates in diastolic heart failure. Currently there is no specific therapy for diastolic heart failure. We made a novel observation that a diet high in fat and sucrose (HFHS) leads to MHD and causes an abnormal increase in the intracellular concentration of sodium (Na) in the heart. It’s known that elevated cytosolic Na may deplete mitochondrial calcium and lead to both decreased ATP and increased damaging reactive oxygen species (ROS) production.
We hypothesize that elevated myocardial Na leads to impaired mitochondrial calcium signaling in MHD. As result, mitochondria produce less ATP and more ROS. Consequently, less ATP is available to fuel cell functions such as relaxation and contraction. Of the two, myocardial relaxation is more susceptible to the lack of ATP, thus diastolic dysfunction ensues.
To test our hypothesis, we will use mice fed HFHS diet that become obese and develop MHD. Our aims will test 1) the role of Na elevation in decreased ATP and increased ROS production, 2) the role of Na-induced decreased ATP production in energetic and contractile dysfunction and 3) the role of Na-induced increased ROS production in mediating MHD.
To address these aims, intracellular Na, mitochondrial calcium and mitochondrial ROS will be manipulated in vitro and ex vivo using a variety of pharmacologic and transgenic interventions. Mitochondrial function and ROS production will be assessed in isolated mitochondria, calcium regulation and function will be assessed in isolated myocytes, and cardiac intracellular Na and energetics will be assessed in beating hearts using 23Na and 31P NMR spectroscopy.
- Comenius University, MD
- Comenius University, PhD
- Published on 2/1/2018
Luptak I, Sverdlov AL, Panagia M, Qin F, Pimentel DR, Croteau D, Siwik DA, Ingwall JS, Bachschmid MM, Balschi JA, Colucci WS. Decreased ATP production and myocardial contractile reserve in metabolic heart disease. J Mol Cell Cardiol. 2018 Feb 01; 116:106-114. PMID: 29409987.
- Published on 8/19/2017
Wende AR, Kim J, Holland WL, Wayment BE, O'Neill BT, Tuinei J, Brahma MK, Pepin ME, McCrory MA, Luptak I, Halade GV, Litwin SE, Abel ED. Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses. Am J Physiol Heart Circ Physiol. 2017 Dec 01; 313(6):H1098-H1108. PMID: 28822962.
- Published on 1/11/2016
Sverdlov AL, Elezaby A, Qin F, Behring JB, Luptak I, Calamaras TD, Siwik DA, Miller EJ, Liesa M, Shirihai OS, Pimentel DR, Cohen RA, Bachschmid MM, Colucci WS. Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease. J Am Heart Assoc. 2016 Jan 11; 5(1). PMID: 26755553.
- Published on 12/31/2015
Miller EJ, Calamaras T, Elezaby A, Sverdlov A, Qin F, Luptak I, Wang K, Sun X, Vijay A, Croteau D, Bachschmid M, Cohen RA, Walsh K, Colucci WS. Partial Liver Kinase B1 (LKB1) Deficiency Promotes Diastolic Dysfunction, De Novo Systolic Dysfunction, Apoptosis, and Mitochondrial Dysfunction With Dietary Metabolic Challenge. J Am Heart Assoc. 2015 Dec 31; 5(1). PMID: 26722122.
- Published on 12/9/2014
Elezaby A, Sverdlov AL, Tu VH, Soni K, Luptak I, Qin F, Liesa M, Shirihai OS, Rimer J, Schaffer JE, Wilson S C, Edward J M. Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload. J Mol Cell Cardiol. 2015 Feb; 79:275-83. PMID: 25497302.
- Published on 8/7/2014
Sverdlov AL, Elezaby A, Behring JB, Bachschmid MM, Luptak I, Tu VH, Siwik DA, Miller EJ, Liesa M, Shirihai OS, Pimentel DR, Cohen RA, Colucci WS. High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II. J Mol Cell Cardiol. 2015 Jan; 78:165-73. PMID: 25109264.
- Published on 12/11/2013
Zhi H, Luptak I, Alreja G, Shi J, Guan J, Metes-Kosik N, Joseph J. Effects of direct Renin inhibition on myocardial fibrosis and cardiac fibroblast function. PLoS One. 2013; 8(12):e81612. PMID: 24349097.
- Published on 8/20/2013
Qin F, Siwik DA, Lancel S, Zhang J, Kuster GM, Luptak I, Wang L, Tong X, Kang YJ, Cohen RA, Colucci WS. Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart. J Am Heart Assoc. 2013 Aug; 2(4):e000184. PMID: 23963753.
- Published on 10/24/2012
Metes-Kosik N, Luptak I, Dibello PM, Handy DE, Tang SS, Zhi H, Qin F, Jacobsen DW, Loscalzo J, Joseph J. Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance. Mol Nutr Food Res. 2012 Dec; 56(12):1812-24. PMID: 23097236.
- Published on 3/2/2012
Qin F, Siwik DA, Luptak I, Hou X, Wang L, Higuchi A, Weisbrod RM, Ouchi N, Tu VH, Calamaras TD, Miller EJ, Verbeuren TJ, Walsh K, Cohen RA, Colucci WS. The polyphenols resveratrol and S17834 prevent the structural and functional sequelae of diet-induced metabolic heart disease in mice. Circulation. 2012 Apr 10; 125(14):1757-64, S1-6. PMID: 22388319.
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