Department of Internal Medicine (Cardiology), School of Medicine
The study of the functional roles of different isoforms of cardiac calcium channels using combined techniques of transgenic mouse models, gene silencing and patch-clamp recordings.
Our laboratory has focused our research efforts in two major areas in cardiovascular diseases. 1. The study of the functional roles of different isoforms of cardiac calcium and calcium-activated potassium channels using combined techniques of transgenic mouse models, gene silencing and patch-clamp recordings. One of the main projects in our laboratory is to utilize multiple approaches to determine the functional significance of the interacting partners of Ca and K channels in atrial myocytes and in so doing, provide new insights into the underlying mechanisms of certain forms of atrial arrhythmias. 2. Roles of soluble epoxide hydrolase (sEH) inhibitors in the prevention of cardiac hypertrophy and failure. Eicosanoids are potent modulators of immune responses and are derived from the 20-carbon atom arachidonic acids (AA). Epoxyeicosatrienoic acids (EETs) are derivatives of arachidonic acid (AA) generated through cytochrome P450 pathway. sEH catalizes the conversion of EETs to form the corresponding dihydroxyeicosatrienoic acids (DHETs). Recently, we have shown that several inhibitors of sEH exert beneficial effects in the prevention of cardiac hypertrophy and failure. Moreover, our study shows a beneficial effect of the compounds in the prevention of cardiac arrhythmias which occur in association with cardiac hypertrophy. Very little is known about the roles of this new class of compounds in the treatment of cardiac hypertrophy and failure. Additional information is urgently needed to establish whether the observed beneficial effects are generalizable to other models of cardiac hypertrophy and failure.
Grad Group Affiliations
- Molecular, Cellular and Integrative Physiology
- Pharmacology and Toxicology
Specialties / Focus
- Cardiorespiratory Physiology
- PGG 210B Advanced Physiology, Winter
- PHA 400C Principles of Pharmacology, Winter
- Genome and Biomedical Science Facility, 6th floor
- Ning Li, Valeriy Timofeyev, Anil Singapuri, Padmini Sirish, Richard Myers, Zheng Zhang, Bert Frederich
Honors and Awards
- Program Director, National Institutes of Health T32 Training Program in Basic and Translational Cardiovascular Sciences
- Co-Director, HHMI Integrating Medicine into Basic Science Training Program
- Society of General Physiologists, Biophysical Society, Council on Basic Cardiovascular Sciences, American Heart Association
- 1984 MD Medicine University of Toronto
- 1980 Science Faculty of Arts and Science, University of Toronto
Ai D, Pang W, Li N, Xu M, Jones PD, Yang J, Zhang Y, Chiamvimonvat N, Shyy JY, Hammock BD, Zhu Y. Soluble epoxide hydrolase plays an essential role in angiotensin II-induced cardiac hypertrophy. Proc Natl Acad Sci U S A. 2009. In press.
Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, Zhang Z, Singapuri A, Albert T, Rajagopal A, Bond CT, Periasamy M, Adelman J, Chiamvimonvat N. Ablation of a Ca-activated K channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol. 2009. In press.
Zhang Q, Timofeyev V, Lu L, Li N, Singapuri A, Long MK, Bond CT, Adelman JP, Chiamvimonvat N. Functional roles of a Ca2+-activated K+ channel in atrioventricular nodes. Circ Res. 2008;102(4):465-471.
Harris TR, Li N, Chiamvimonvat N, Hammock BD. The potential of soluble epoxide hydrolase inhibition in the treatment of cardiac hypertrophy. Congest Heart Fail. 2008;14(4):219-224.
Chen CY, Chow D, Chiamvimonvat N, Glatter KA, Li N, He Y, Pinkerton KE, Bonham AC. Short-term secondhand smoke exposure decreases heart rate variability and increases arrhythmia susceptibility in mice. Am J Physiol Heart Circ Physiol. 2008;295(2):H632-639.
Chiamvimonvat N, Ho CM, Tsai HJ, Hammock BD. The soluble epoxide hydrolase as a pharmaceutical target for hypertension. J Cardiovasc Pharmacol. 2007;50(3):225-237.
Lu L, Zhang Q, Timofeyev V, Zhang Z, Young JN, Shin HS, Knowlton AA, Chiamvimonvat N. Molecular coupling of a Ca2+-activated K+ channel to L-type Ca2+ channels via alpha-actinin2. Circ Res. 2007;100(1):112-120
Xu Y, Zhang Q, Chiamvimonvat N. IK1 and cardiac hypoxia: after the long and short QT syndromes, what else can go wrong with the inward rectifier K+ currents? J Mol Cell Cardiol. 2007;43(1):15-17.
Glatter KA, Hamdan MH, Zhang Q, Chiamvimonvat N. Drug-induced long QT syndrome: a continuing challenge in the field. J Cardiovasc Electrophysiol. 2007;18(7):696-697.
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. A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice. Cardiovasc Res. 2007;75(1):69-78.
Babu GJ, Bhupathy P, Timofeyev V, Petrashevskaya NN, Reiser PJ, Chiamvimonvat N, Periasamy M. Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility. Proc Natl Acad Sci U S A. 2007;104(45):17867-17872.
Viitasalo M, Oikarinen L, Swan H, Glatter KA, Vaananen H, Fodstad H, Chiamvimonvat N, Kontula K, Toivonen L, Scheinman MM. Ratio of late to early T-wave peak amplitude in 24-h electrocardiographic recordings as indicator of symptom history in patients with long-QT Syndrome types 1 and 2. J Am Coll Cardiol. 2006;47:112-20.
Xu D, Li N, He Y, Timofeyev V, Lu L, Tsai HJ, Kim IH, Tuteja D, Mateo RK, Singapuri A, Davis BB, Low R, Hammock BD, Chiamvimonvat N. Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors. Proc Natl Acad Sci U S A. 2006;103(49):18733-18738.
Timofeyev V, He Y, Tuteja D, Zhang Q, Roth DM, Hammond HK, Chiamvimonvat N. Cardiac-directed expression of adenylyl cyclase reverses electrical remodeling in cardiomyopathy. J Mol Cell Cardiol. 2006;41(1):170-181.
Kamp TJ, Chiamvimonvat N. Mission impossible: IGF-1 and PTEN specifically "Akt"ing on cardiac L-type Ca2+ channels. Circ Res. 2006;98(11):1349-1351.
Nie L, Song H, Chen MF, Chiamvimonvat N, Beisel KW, Yamoah EN, Vazquez AE. Cloning and expression of a small-conductance Ca(2+)-activated K+ channel from the mouse cochlea: coexpression with alpha9/alpha10 acetylcholine receptors. J Neurophysiol. 2004;91:1536-44.
Zhang Z, He Y, Tuteja D, Xu D, Timofeyev V, Zhang Q, Glatter KA, Xu Y, Shin HS, Low R, Chiamvimonvat N. Functional roles of Cav1.3(alpha1D) calcium channels in atria: insights gained from gene-targeted null mutant mice. Circulation. 2005;112:1936-44.
Tuteja D, Xu D, Timofeyev V, Lu L, Sharma D, Zhang Z, Xu Y, Nie L, Vazquez AE, Young JN, Glatter KA, Chiamvimonvat N. Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol. 2005;289:H2714-23.
Xu Y, Zhang Z, Timofeyev V, Sharma D, Xu D, Tuteja D, Dong PH, Ahmmed GU, Ji Y, Shull GE, Periasamy M, Chiamvimonvat N. The effects of intracellular Ca2+ on cardiac K+ channel expression and activity: novel insights from genetically altered mice. J Physiol. 2005;562:745-58.
Sharma D, Glatter KA, Timofeyev V, Tuteja D, Zhang Z, Rodriguez J, Tester DJ, Low R, Scheinman MM, Ackerman MJ, Chiamvimonvat N. Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: implications for genetic testing. J Mol Cell Cardiol. 2004;37:79-89.
Glatter KA, Chiamvimonvat N. Tachy- or bradyarrhythmias: Implications for therapeutic intervention in LQT3 families. Circulation Research. 92: 941-943, 2003. Zhang Z, Xu Y, Dong PH, Sharma D, Chiamvimonvat N. A negatively charged residue in the outer mouth of rat sodium channels determine the gating kinetics of the channels. Am J Physiol Cell Physiol 284:C1247-C1254, 2003. Chiamvimonvat N. Diastolic dysfunction and the aging heart. Journal of Molecular and Cellular Cardiology 34:607-610, 2002.
Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, Vazquez AE, Yamoah EN, Chiamvimonvat N. Molecular identification and functional roles of a Ca-activated K channel in human and mouse hearts. J Biol Chem. 278:49085-94, 2003.
Xu Y, Chiamvimonvat N, Akunuru S, Ratner N, Yamoah EN. Gene-targeted deletion of neurofibromin enhances the expression of a transient outward K+ current in Schwann cells: a protein kinase A-mediated mechanism. Journal of Neuroscience 22:9194-202, 2002. Xu Y, Dong PH, Ahmmed GA, Chiamvimonvat N. Functional roles of the calcium-activated chloride current in mouse ventricular myocytes. American Journal of Physiology 283:H302-H314, 2002. Zhang Z, Xu Y, Song H, Rodriguez J, Tuteja D, Namkung Y, Shin HS, Chiamvimonvat N. Functional roles of a1D calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice. Circulation Research 90:981-987, 2002. Ahmmed GU, Xu Y, Dong PH, Zhang Z, Eiserich J, Chiamvimonvat N. Nitric oxide modulates cardiac sodium channel via protein kinase A and protein kinase G. Circulation Research 89:1005-1013, 2001. Ahmmed GU, Dong PH, Song G, Ball NA, Xu Y, Walsh RA, Chiamvimonvat N. Changes In Ca2+ cycling proteins underlie cardiac action potential prolongation in a pressure overloaded guinea pig model with cardiac hypertrophy and failure. Circulation Research 86:558-570, 2000. Ji Y, Lalli MJ, Babu GJ, Xu Y, Kirkpatrick DL, Liu LH, Chiamvimonvat N, Walsh RA, Shull GE, Periasamy M. Disruption of a single copy of the SERCA2 gene results in altered Ca2+ homeostasis and cardiomyocyte function. Journal of Biological Chemistry 275:38073-38080, 2000. Li RA, Velez P, Chiamvimonvat N, Tomaselli G, Marban E. Contributions to permeation of charged residues between the selectivity filter and S6 segments in the rat skeletal muscle (m1-2) Na+ channel. Journal of General Physiology 115:81-92. 1999.