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.
- Member, Whitaker Cardiovascular Institute, Boston University
- Comenius University, MD
- Comenius University, PhD
- Published on 7/8/2020
Panagia M, Yang J, Gale E, Wang H, Luptak I, Chen HH, Patel D, Croteau D, Pimentel DR, Bachschmid MM, Colucci WS, Ran C, Sosnovik DE. A novel tracer for in vivo optical imaging of fatty acid metabolism in the heart and brown adipose tissue. Sci Rep. 2020 Jul 08; 10(1):11209. PMID: 32641756.
- Published on 2/17/2020
Panagia M, He H, Baka T, Pimentel DR, Croteau D, Bachschmid MM, Balschi JA, Colucci WS, Luptak I. Increasing mitochondrial ATP synthesis with butyrate normalizes ADP and contractile function in metabolic heart disease. NMR Biomed. 2020 05; 33(5):e4258. PMID: 32066202.
- Published on 9/19/2019
Kimura T, Ferran B, Tsukahara Y, Shang Q, Desai S, Fedoce A, Pimentel DR, Luptak I, Adachi T, Ido Y, Matsui R, Bachschmid MM. Production of adeno-associated virus vectors for in vitro and in vivo applications. Sci Rep. 2019 09 19; 9(1):13601. PMID: 31537820.
- Published on 7/9/2019
Luptak I, Morgan R, Baka T, Croteau D, Moverman D, Sarnak H, Kirber M, Bachschmid MM, Colucci WS, Pimentel DR. Genetically targeted fluorescent probes reveal dynamic calcium responses to adrenergic signaling in multiple cardiomyocyte compartments. Int J Biochem Cell Biol. 2019 09; 114:105569. PMID: 31299273.
- Published on 7/1/2019
Luptak I, Croteau D, Valentine C, Qin F, Siwik DA, Remick DG, Colucci WS, Hobai IA. Myocardial Redox Hormesis Protects the Heart of Female Mice in Sepsis. Shock. 2019 07; 52(1):52-60. PMID: 30102640.
- Published on 6/25/2019
Luptak I, Qin F, Sverdlov AL, Pimentel DR, Panagia M, Croteau D, Siwik DA, Bachschmid MM, He H, Balschi JA, Colucci WS. Energetic Dysfunction Is Mediated by Mitochondrial Reactive Oxygen Species and Precedes Structural Remodeling in Metabolic Heart Disease. Antioxid Redox Signal. 2019 09 01; 31(7):539-549. PMID: 31088291.
- Published on 4/9/2019
Yunis A, Doros G, Luptak I, Connors LH, Sam F. Use of Ventilatory Efficiency Slope as a Marker for Increased Mortality in Wild-Type Transthyretin Cardiac Amyloidosis. Am J Cardiol. 2019 07 01; 124(1):122-130. PMID: 31053293.
- Published on 3/1/2018
Panagia M, Chen HH, Croteau D, Iris Chen YC, Ran C, Luptak I, Josephson L, Colucci WS, Sosnovik DE. Multiplexed Optical Imaging of Energy Substrates Reveals That Left Ventricular Hypertrophy Is Associated With Brown Adipose Tissue Activation. Circ Cardiovasc Imaging. 2018 03; 11(3):e007007. PMID: 29555834.
- 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 03; 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.
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