INDIVIDUAL RESEARCHERYong-Xiao Wang , M.D. , Ph.D.
Education1990 - Ph.D. from Fourth Military Medical University, China
1983 - M.D. from Wannan Medical College, China
Cellular calcium, ion channels, reactive oxygen species and neurotransmitter receptors are the important signal transduction elements in the cell. These elements may initiate, regulate and maintain a variety of cellular responses such as cell contraction, proliferation, migration, differentiation, gene expression, metabolism and death. Our main research interests are focused on the studies of their molecular geneses, regulatory mechanisms, signaling processes, and physiological roles in vascular, airway, and other muscle cells. We also seek to determine the functional importance of these signal transduction constituents in the development of pulmonary hypertension, asthma, diabetes and hypertension. We pursue these goals using laser scanning confocal microscopic, wide-field calcium imaging, patch clamp, biochemical, molecular biological, pharmacological and genetic (e.g., gene knockdown, knockout and overexpression) approaches at the molecular, cellular, organ and animal levels alongside tissues and cells from patients.
The ongoing research projects in the laboratory include (but not limited):
1) Mechanisms for hypoxic calcium release in pulmonary artery myocytes Intracellular Ca2+ release in smooth muscle cells plays a crucial role in the development of hypoxia-induced pulmonary vasoconstriction and associated pulmonary hypertension, but cellular and molecular processes coupling hypoxia to Ca2+ release are poorly understood. In this research project, we attempt to determine: 1) how hypoxia induces Ca2+ release from intracellular stores; and 2) what the primary oxygen sensors and key signal transducing elements are in hypoxic Ca2+ release. Specifically, we are focused on the roles of ryanodine receptors, inositol triphosphate receptors, FK506 binding protein 12, cyclic ADP-ribose, nicotinic acid adenine dinucleotide phosphate, mitochondria, NADPH oxidase, reactive oxygen species, redox potential and protein kinase C in hypoxic Ca2+ release in pulmonary artery myocytes.
2) Novel signaling for calcium release in airway myocytes Cholinergic nerves provide a predominant neural control of airway smooth muscle cells through muscarinic receptors. Simulation of these receptors activates phospholipase C, and then generates inositol triphosphate, which induces Ca2+ release from the sarcoplasmic reticulum through inositol triphosphate receptors. This research proposal seeks to examine whether: 1) stimulation of muscarinic receptors may result in the activation of ADP-ribosyl cyclase, production of cyclic ADP-ribose, and Ca2+ release through ryanodine receptors, amplifying muscarinic Ca2+ release and associated contraction in airway smooth muscle cells; and 2) the ADP-ribosyl cyclase/cyclic ADP-ribose signaling may contribute to asthmatic airway muscle hyperresponsiveness to muscarinic agonists.
3) Heterogeneity of hypoxic calcium release in pulmonary and systemic artery myocytes Hypoxia induces vasoconstriction in pulmonary arteries, but not systemic arteries. Moreover, hypoxic pulmonary vasoconstriction is much greater in resistance than conduit pulmonary arteries. This research project aims to examine if: 1) subtype ryanodine receptors (RyR1, RyR2 and RyR3) are heterogeneously expressed in resistance and conduit pulmonary as well as systemic artery smooth muscle cells; 2) the heterogeneity in subtype RyR expression underlies functional differences in excitation-contraction coupling and hypoxic Ca2+ release between these cell types; and 3) specific interactions of FK506 binding proteins and cyclic ADP-ribose with different subtype RyRs may play an important role in the functional differences.
4) Expression and roles of FK506 binding protein 12.6 in pulmonary artery myocytes FK506 binding proteins with molecular weights of 12 and 12.6 KDa (FKBP12 and FKBP12.6) are associated with and regulate the skeletal and cardiac ryanodine receptors, respectively. However, little is known about the expression and functions of FKBPs in smooth muscle cells. Our main interests in this proposal are to study: 1) whether FKBP12.6 is expressed and plays a role in hypoxic Ca2+ release in pulmonary artery myocytes; and 2) whether cyclic ADP-ribose mediates the role of FKBP12.6 in hypoxic Ca2+ release in pulmonary artery smooth muscle cells.
- Wang YX, Korth M. Effects of doxorubicin on excitation-contraction coupling in guinea pig ventricular myocardium. Circ Res. 1995 Apr;76(4):645-53.
- Xin HB, Senbonmatsu T, Cheng DS, Wang YX, Copello JA, Ji GJ, Collier ML, Deng KY, Jeyakumar LH, Magnuson MA, Inagami T, Kotlikoff MI, Fleischer S. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature. 2002 Mar 21;416(6878):334-8.
- Liu QH, Zheng YM, Korde AS, Yadav VR, Rathore R, Wess J, Wang YX. Membrane depolarization causes a direct activation of G protein-coupled receptors leading to local Ca2+ release in smooth muscle. Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11418-23.
- Wang YX, Zheng YM. Role of ROS signaling in differential hypoxic Ca2+ and contractile responses in pulmonary and systemic vascular smooth muscle cells. Respir Physiol Neurobiol. 2010 Dec 31;174(3):192-200
- Wang YX, Zheng YM. ROS-dependent signaling mechanisms for hypoxic Ca(2+) responses in pulmonary artery myocytes. Antioxid Redox Signal. 2010 Mar 1;12(5):611-23.
- Liao B, Zheng YM, Yadav VR, Korde AS, Wang YX. Hypoxia induces intracellular Ca2+ release by causing reactive oxygen species-mediated dissociation of FK506-binding protein 12.6 from ryanodine receptor 2 in pulmonary artery myocytes. Antioxid Redox Signal. 2011 Jan 1;14(1):37-47.
- Wang YX, Zheng YM. Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells. Adv Exp Med Biol. 2011;704:731-47.
- Yadav VR, Zheng YM, Wang YX. Essential role of phospholipase C-gamma1 in hypoxia-induced pulmonary vasoconstriction and hypertension. J Membra Sci Technol. 2013 June 18;3:e115
- Zheng YM, Park SW, Stokes L, Tang Q, Xiao JH, Wang YX. Distinct activity of BK channel ?1-subunit in cerebral and pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol. 2013 Apr 15;304(8):C780-9.
- Yadav VR, Song T, Joseph L, Mei L, Zheng YM, Wang YX. Important role of PLC-gamma1 in hypoxic increase in intracellular calcium in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2013 Feb 1;304(3):L143-51.
- Korde AS, Yadav VR, Zheng YM, Wang YX. Primary role of mitochondrial Rieske iron-sulfur protein in hypoxic ROS production in pulmonary artery myocytes. Free Radic Biol Med. 2011 Apr 15;50(8):945-52.
- Mei L, Wang YX & Zheng YM. Ryanodine and inositol trisphosphate receptor Ca2+ release channels in airway smooth muscle cells (Chapter 1). In: Wang YX, ed. Calcium signaling in airway smooth muscle cells. New York City: Springer Verlag; 1-20, 2013.
- Xiao JH, Zheng YM & Wang YX. TRP and Orai channels in airway smooth muscle cells (Chapter 3). In: Wang YX, ed. Calcium signaling in airway smooth muscle cells. New York City: Springer Verlag; 35-48, 2013.
- Liu QH, Savoia C, Zheng YM & Wang YX. Local calcium signaling in airway smooth muscle cells (Chapter 6). In: Wang YX, ed. Calcium signaling in airway smooth muscle cells. New York City: Springer Verlag; 107-124, 2013.
- Song TY, Wang YX & Zheng YM. Calcium signaling in airway smooth muscle remodeling(Chapter 22). In: Wang YX, ed. Calcium signaling in airway smooth muscle cells. New York City: Springer Verlag; 393-407, 2013.
- Zheng YM & Wang YX. Ryanodine receptors/Ca2+ release channels in pulmonary artery smooth muscle cells. In: Wang YX, ed. Recent advances in pulmonary vascular biology. Trivandrum, Kerala: Research Signpost; 91-114, 2011.