Sergiy Viatchenko-Karpinski, Ph.D.
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Research Assistant Professor
505 Davis Heart & Lung Research Institute
473 W. Twelfth Avenue
Columbus OH 43210
614-688-4250
Serge.Karpinski@osumc.edu |
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Education:
Ph.D., Biophysics, Bogomoletz Institute of Physiology, Ukrainian National Academy of Science, Kiev, Ukraine.
Research Area:
Cardiovascular physiology, calcium-induced calcium release in cardiac muscle, altered excitation-contraction coupling in heart failure, ventricular arrhythmia development, calcium handling mechanisms in early cardiac development.
Current Research Projects:
• Regulation of calcium-induced calcium release (CICR) in cardiomyocytes by luminal proteins. Mechanisms of ventricular arrhythmia development associated with mutations of calsequestrin (CSQ).
• Altered CICR in chronic heart failure and diabetes.
• Calcium handling in early cardiac development. Cardiac arrhythmia associated with different mechanisms of cell contraction in the differentiating myocytes.
Recently our laboratory has shown that in cardiac muscle, the sarcoplasmic reticulum (SR) calcium (Ca) release channels/ryanodine receptors (RyRs) that are positively controlled by Ca levels inside the SR through a luminal Ca sensor. This process, termed luminal Ca-dependent deactivation, represents the negative feedback mechanism to control CICR in the heart. We provided the evidence that mutations in human cardiac CSQ, a high-capacity calcium binding protein located in the SR link to effort-induced ventricular arrhythmia and sudden death (Catecholaminergic polymorphic ventricular tachycardia, CPVT). We identified two mechanisms by which CSQ mutations can lead to CPVT: 1) impairment of CSQ expression/Ca binding activity affects RyR indirectly by altering the dynamics of free Ca; 2) disruption of interaction of CSQ with the RyR complex.
Stem cell plasticity and the ability of stem cells to regenerate the myocardium after injury is an area of growing interest. Development of arrhythmias in regenerated regions is among the most important issues in cell regeneration therapy. Previously we shown that early development stage cardiomyocytes rely on a unique mechanism for their contractile activation mediated by intracellular Ca oscillations. Since these oscillations could lead to disruption of the normal cardiac rhythm it is important to understand how they are generated. The results of our experiments suggest that intracellular calcium oscillations in early cardiogenesis are governed by P2Y purinoreceptor-mediated Ca release via InsP3Rs and that RyRs Ca stores although present do not play a significant role in generation of Ca oscillations and early cardiac contractility.
Our most recent experiments show, that luminal Ca regulatory proteins CSQ and triadin are not expressed in early cardiogeneses. Adenovirus-mediated expression of CSQ in ES cells does not change efficiency of in vitro ES cells differentiation to cardiomyocytes, but modulates caffeine induced Ca release. Moreover, single elementary Ca release events (RyR mediated Ca release) – Ca sparks are not present in early cardiac myocytes, but appear in cardiac myocytes divided from CSQ transfected ES cells. InsP3R mediated Ca release was not changed on the whole cell level and on the level of Ca puffs. These results indicate that cardiac specific RyR mediated Ca release develops in cardiogeneses independent from InsP3R mediated Ca release. RyR signaling could be used as a target for modulation of spontaneous Ca oscillations in early cardiac development.
Techniques Available:
Electrophysiological (patch clamp) recordings from single cardiac myocytes; fluorescent optical imaging of intracellular calcium dynamics; differentiation in vitro cardiomyocytes from embryonic stem cells.
Selected Publications:
• Hussain SR, Lucas DM, Johnson AJ, Lin TS, Bakaletz AP, Dang VX, Viatchenko-Karpinski S, Ruppert AS, Byrd JC, Kuppusamy P, Crouser ED, Grever MR. (2008) Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium. Blood. 2008 Jan 11; [Epub ahead of print] PMID: 18192508.
• Nishijima Y, Sridhar A, Viatchenko-Karpinski S, Shaw C, Bonagura JD, Abraham WT, Joshi MS, Bauer JA, Hamlin RL, Gyorke S, Feldman DS, Carnes CA. (2007) Chronic cardiac resynchronization therapy and reverse ventricular remodeling in a model of nonischemic cardiomyopathy. Life Sci; 81:1151-1159.
• Lacombe VA, Viatchenko-Karpinski S, Terentyev D, Sridhar A, Emani S, Bonagura JD, Feldman DS, Gyorke S, Carnes CA. (2007) Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes.Am J Physiol Regul Integr Comp Physiol; 293:R1787-R1797.
• Dirksen WP, Lacombe VA, Chi M, Kalyanasundaram A, Viatchenko-Karpinski S, Terentyev D, Zhou Z, Vedamoorthyrao S, Li N, Chiamvimonvat N, Carnes CA, Franzini-Armstrong C, Gyorke S, Periasamy M. (2007) A Mutation in Calsequestrin, CASQ2D307H, Impairs Sarcoplasmic Reticulum Ca2+ Handling and Causes Complex Ventricular Arrhythmias in mice. Cardiovascular Research, 75:69-78.
• di Barletta MR, Viatchenko-Karpinski S, Nori A, Memmi M, Terentyev D, Turcato F, Valle G, Rizzi N, Napolitano C, Gyorke S, Volpe P, and Priori SG. (2006) Clinical Phenotype and Functional Characterization of CASQ2 Mutations Associated With Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation, 114: 1012 - 1019.
• Kubalova Z, Terentyev D, Viatchenko-Karpinski S, Nishijima Y, Gyorke I, Terentyeva R, da Cunha D, Sridhar A, Feldman DS, Hamlin RL, Carnes CA, Gyorke S. Abnormal intrastore calcium signaling in chronic heart failure. Proc Natl Acad Sci USA, 102(39):14104-14109, 2005.
• Viatchenko-Karpinski S, Terentyev D, Jenkins LA, Lutherer LO, Gyorke S. Synergistic Interactions between Ca2+ Entries through L-Type Ca2+ Channels and Na+-Ca2+ Exchanger in Normal and Failing Heart. J Physiol, 567: 493-504, 2005.
• Fleishmann BK, Duan Y, Fan Y, Schoneberg T, Ehlich A, Lenka N, Viatchenko-Karpinski S, Pott L, Hescheler J, Fakler B. Differential subunit composition of the G-protein activated inward-rectifier K channel during cardiac development. J Clin Invest, 114: 994-1001, 2004.
• Viatchenko-Karpinski S, Terentyev D, Gyorke I, Terentyeva R, Volpe P, Priori SG, Napolitano C, Nori A, Williams SC, Gyorke S. Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin. Circ Res, 94(4):471-477, 2004.
• Terentyev D, Viatchenko-Karpinski S, Gyorke I, Volpe P, Williams SC, Gyorke S. Calsequestin determines the functional size and stability of cardiac sarcoplasmic reticulum calcium stores. Proc Natl Acad Sci USA, 100(20):11759-11764, 2003.
• Viatchenko-Karpinski S, Györke S. Modulation of the Ca2+-induced Ca2+ release cascade by -adrenergic stimulation in rat ventricular myocytes. J Physiol, 533(3): 837-848, 2001.
• Viatchenko-Karpinski S, Fleischmann BK, Liu Q, Sauer H, Gryshchenko O, Ji GJ, Hescheler J. Intracellular Ca2+ oscillations drive spontaneous contractions in cardiomyocytes during early development. Proc Natl Acad Sci USA, 96(14): 8259-64, 1999.
Research Funding:
• American Heart Association, National Center Research Program Scientist Development Grant ($260,000). Altered adrenergic modulation of sarcoplasmic reticulum calcium release in myopathy induced by chronic treatment with isoproterenol. 07/2004-06/2008.
• NIH R01 HL084498-01A2. Adrenergically mediated remodeling in non-ischemic heart failure. PI: David S Feldman, Co- PI: Terry S Elton, Sergiy Viatchenko-Karpinski, Mark T Ziolo. 07/01/2007 - 06/30/2012.
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