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INDIVIDUAL RESEARCHER

Yong-Xiao Wang , M.D. , Ph.D.

e-mail: wangy@mail.amc.edu


Education

1990 - Ph.D. from Fourth Military Medical University, China
1983 - M.D. from Wannan Medical University, China


Current Research

Intracellular Ca2+ acts as a key signal to initiate and maintain numerous cellular functions. The Ca2+ signaling has spatiotemporal patterns and levels, which are generated and controlled by intracellular Ca2+ release channels and plasmalemmal Ca2+-permeable channels. Our main research interests are to define: 1) the cellular and molecular mechanisms that control and regulate intracellular Ca2+ release and plasmalemmal Ca2+ influx, 2) the roles of intracellular Ca2+ as a signal in cellular responses, and 3) the cellular and molecular processes coupling Ca2+ signaling to Ca2+-activated ion channels, particularly in smooth muscle cells under physiological and pathological conditions. We pursue these goals using laser scanning confocal microscopic, wide-field calcium imaging, patch clamp, biochemical, molecular biological, and genetic (e.g., gene overexpression and knockout) approaches. The ongoing funded research projects in the laboratory include:
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.



PubMed Publications

  1. 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.


  2. 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.


  3. 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.


  4. 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.


  5. 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.



References

  1. 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.


  2. 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.


  3. Wang YX, Zheng YM. ROS-dependent signaling mechanisms for hypoxic Ca2+ responses in pulmonary artery myocytes. Antioxid Redox Signal. 2010 Mar 1;12(5):611-23.


  4. 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.


  5. 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.