Keywords
Last Name

Ivan Luptak, MD, PhD

TitleAssistant Professor
InstitutionBoston University School of Medicine
DepartmentMedicine
DivisionCardiovascular Medicine
Address650 Albany St Evans Biomed Research Ctr
Boston MA
 Awards and Honors

Start-EndDescription
2015-2020American Heart Association: Fellow to Faculty Transition Award
 Research Expertise & Professional Interests
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.

 Self-Described Keywords
  • mitochondria
  • energetic metabolism
  • ATP
  • obesity
  • NMR spectroscopy
  • cardiomyopathy
  • heart failure
  • intracellular sodium
  • diastolic dysfunction
 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. 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.
    View in: PubMed
  2. 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.
    View in: PubMed
  3. 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.
    View in: PubMed
  4. 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.
    View in: PubMed
  5. 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.
    View in: PubMed
  6. 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.
    View in: PubMed
  7. 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.
    View in: PubMed
  8. 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.
    View in: PubMed
  9. Bugger H, Riehle C, Jaishy B, Wende AR, Tuinei J, Chen D, Soto J, Pires KM, Boudina S, Theobald HA, Luptak I, Wayment B, Wang X, Litwin SE, Weimer BC, Abel ED. Genetic loss of insulin receptors worsens cardiac efficiency in diabetes. J Mol Cell Cardiol. 2012 May; 52(5):1019-26. PMID: 22342406.
    View in: PubMed
  10. Liesa M, Luptak I, Qin F, Hyde BB, Sahin E, Siwik DA, Zhu Z, Pimentel DR, Xu XJ, Ruderman NB, Huffman KD, Doctrow SR, Richey L, Colucci WS, Shirihai OS. Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion. Circulation. 2011 Aug 16; 124(7):806-13. PMID: 21788586.
    View in: PubMed
  11. Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I, O'Shea KM, Riley DD, Lugus JJ, Colucci WS, Lederer WJ, Stanley WC, Walsh K. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol. 2011 Mar; 31(6):1309-28. PMID: 21245373.
    View in: PubMed
  12. Luptak I, Yan J, Cui L, Jain M, Liao R, Tian R. Long-term effects of increased glucose entry on mouse hearts during normal aging and ischemic stress. Circulation. 2007 Aug 21; 116(8):901-9. PMID: 17679614.
    View in: PubMed
  13. Luptak I, Shen M, He H, Hirshman MF, Musi N, Goodyear LJ, Yan J, Wakimoto H, Morita H, Arad M, Seidman CE, Seidman JG, Ingwall JS, Balschi JA, Tian R. Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage. J Clin Invest. 2007 May; 117(5):1432-9. PMID: 17431505.
    View in: PubMed
  14. Arikawa E, Ma RC, Isshiki K, Luptak I, He Z, Yasuda Y, Maeno Y, Patti ME, Weir GC, Harris RA, Zammit VA, Tian R, King GL. Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. Diabetes. 2007 May; 56(5):1410-20. PMID: 17363743.
    View in: PubMed
  15. Matsui T, Nagoshi T, Hong EG, Luptak I, Hartil K, Li L, Gorovits N, Charron MJ, Kim JK, Tian R, Rosenzweig A. Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab. 2006 May; 290(5):E789-97. PMID: 16352665.
    View in: PubMed
  16. Luptak I, Balschi JA, Xing Y, Leone TC, Kelly DP, Tian R. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation. 2005 Oct 11; 112(15):2339-46. PMID: 16203912.
    View in: PubMed
  17. Simko F, Luptak I, Matuskova J, Krajcirovicova K, Sumbalova Z, Kucharska J, Gvozdjakova A, Simko J, Babal P, Pechanova O, Bernatova I. L-arginine fails to protect against myocardial remodelling in L-NAME-induced hypertension. Eur J Clin Invest. 2005 Jun; 35(6):362-8. PMID: 15948896.
    View in: PubMed
  18. Simko F, Pelouch V, Torok J, Luptak I, Matuskova J, Pechanova O, Babal P. Protein remodeling of the heart ventricles in hereditary hypertriglyceridemic rat: effect of ACE-inhibition. J Biomed Sci. 2005; 12(1):103-11. PMID: 15864743.
    View in: PubMed
  19. Simko F, Matuskova J, Luptak I, Krajcirovicova K, Kucharska J, Gvozdjakova A, Babal P, Pechanova O. Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension. Life Sci. 2004 Jan 23; 74(10):1211-24. PMID: 14697405.
    View in: PubMed
  20. Xing Y, Musi N, Fujii N, Zou L, Luptak I, Hirshman MF, Goodyear LJ, Tian R. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem. 2003 Aug 1; 278(31):28372-7. PMID: 12766162.
    View in: PubMed
  21. Liao R, Jain M, Cui L, D'Agostino J, Aiello F, Luptak I, Ngoy S, Mortensen RM, Tian R. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation. 2002 Oct 15; 106(16):2125-31. PMID: 12379584.
    View in: PubMed
  22. Simko F, Luptak I, Matuskova J, Babal P, Pechanova O, Bernatova I, Hulin I. Heart remodeling in the hereditary hypertriglyceridemic rat: effect of captopril and nitric oxide deficiency. Ann N Y Acad Sci. 2002 Jun; 967:454-62. PMID: 12079874.
    View in: PubMed
  23. Skalova K, Luptak I, Turcani M, Hulin I. Adenosine and cardioprotection: what can we learn from nature's genetic polymorphism? Bratisl Lek Listy. 2002; 103(6):187-93. PMID: 12448564.
    View in: PubMed
  24. Mladosievicova B, Foltinova A, Luptak I, Petrasova H, Hulin I. Frequency-domain analysis of the QRS complex after treatment of childhood cancer with anthracycline cytostatics. Pediatr Cardiol. 2001 Nov-Dec; 22(6):478-82. PMID: 11894149.
    View in: PubMed
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