Regulation of Vascular BK Channel in Diabetes

Summary

Principal Investigator: Hon Chi Lee
Abstract: DESCRIPTION (provided by applicant): The large conductance calcium-activated potassium (BK) channels are major ionic determinants in mediating vasorelaxation and are the target of endothelium-derived hyperpolarizing factors (EDHFs). We found that regulation of BK channels by EDHFs is abnormal in diabetic animals and the intrinsic properties of BK channels are altered in diabetic coronary arteries. The BK channels in coronary arterial smooth muscle cells from diabetic animals have reduced sensitivity to calcium- and voltage-dependent activation. We have demonstrated that the mechanism whereby vascular BK channel regulation is altered in Type 1 and Type II diabetes involves hyperglycemia-induced oxidative stress, where the cysteine residues in BK channels are targets of redox modulation. The C911 residue of the BK channel pore subunit is particularly sensitive to modulation by hyperglycemia and by hydrogen peroxide, as the C911A mutation is insensitive to the effects of hydrogen peroxide and to high glucose. The goal of this project is to further delineate the molecular mechanisms through which reactive oxygen species (ROS) modulate BK channels in diabetes. The hypotheses to be tested are: 1) Abnormal vascular BK channel function in diabetes is due to redox modulation of specific cysteine residues by ROS. 2) BK channel modified by ROS is a substrate for ubiquitination and proteasomal degradation. Three specific aims are proposed. Aim 1 will examine the mechanism of BK channel modulation by diabetes-induced oxidative stress. Aim 2 will examine whether prevention of oxidative modulation of specific cysteine residues would maintain the integrity of BK channel function in diabetes. Aim 3 will determine whether redox-modulated BK channels are targets for ubiquitination and proteasomal degradation. These studies will be performed using in vitro and in vivo models of diabetes. Whole-cell and single channel patch clamp techniques, antioxidant enzyme in vitro gene transfer, and specific transgenic mice will be employed to determine the effects of diabetes-induced ROS production on BK channel function and degradation. The results of this project may provide important novel insight into the electrophysiological and molecular mechanisms of altered BK channel function that may contribute to both endothelium-dependent and -independent vascular dysfunction in diabetes.
Funding Period: 2009-07-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Proteomic Analysis of Vascular Endothelial Cells-Effects of Laminar Shear Stress and High Glucose
    Xiao Li Wang
    Departments of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
    J Proteomics Bioinform 2:445. 2009
  2. pmc Regulation of coronary arterial BK channels by caveolae-mediated angiotensin II signaling in diabetes mellitus
    Tong Lu
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    Circ Res 106:1164-73. 2010
  3. pmc Muscle-specific f-box only proteins facilitate bk channel β(1) subunit downregulation in vascular smooth muscle cells of diabetes mellitus
    Dai Min Zhang
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
    Circ Res 107:1454-9. 2010
  4. pmc Autoantibodies and cardiac arrhythmias
    Hon Chi Lee
    Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA
    Heart Rhythm 8:1788-95. 2011
  5. pmc Regulation of the SK3 channel by microRNA-499--potential role in atrial fibrillation
    Tian you Ling
    Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People s Republic of China
    Heart Rhythm 10:1001-9. 2013
  6. pmc Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome
    Xiao Li Wang
    Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Transl Res 162:34-44. 2013

Research Grants

  1. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
  2. Redox Regulation of SERCA by Nitric Oxide
    Richard A Cohen; Fiscal Year: 2013
  3. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  5. Oxidant stress and diabetic endothelial dysfunction
    Ming Hui Zou; Fiscal Year: 2013
  6. ASCORBIC ACID FUNCTION AND METABOLISM
    James M May; Fiscal Year: 2013
  7. Peroxynitrite, protein nitration and advanced diabetic neuropathy
    Mark A Yorek; Fiscal Year: 2013
  8. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  9. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  10. Reactive nitrogen species and accelerated atherosclerosis in type I diabetes
    Ming Hui Zou; Fiscal Year: 2013

Detail Information

Publications6

  1. pmc Proteomic Analysis of Vascular Endothelial Cells-Effects of Laminar Shear Stress and High Glucose
    Xiao Li Wang
    Departments of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
    J Proteomics Bioinform 2:445. 2009
    ..These results were validated by Western blot analysis, suggesting that HG importantly modulates shear stress-mediated endothelial function...
  2. pmc Regulation of coronary arterial BK channels by caveolae-mediated angiotensin II signaling in diabetes mellitus
    Tong Lu
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    Circ Res 106:1164-73. 2010
    ..However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined...
  3. pmc Muscle-specific f-box only proteins facilitate bk channel β(1) subunit downregulation in vascular smooth muscle cells of diabetes mellitus
    Dai Min Zhang
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
    Circ Res 107:1454-9. 2010
    ..The ubiquitin-proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β(1) downregulation in diabetic vessels is unknown...
  4. pmc Autoantibodies and cardiac arrhythmias
    Hon Chi Lee
    Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA
    Heart Rhythm 8:1788-95. 2011
    ..This article will review the current evidence for the role of autoantibodies in the development of cardiac arrhythmias...
  5. pmc Regulation of the SK3 channel by microRNA-499--potential role in atrial fibrillation
    Tian you Ling
    Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People s Republic of China
    Heart Rhythm 10:1001-9. 2013
    ..Recently, KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF...
  6. pmc Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome
    Xiao Li Wang
    Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Transl Res 162:34-44. 2013
    ..Our results suggest that cardiac lipid raft-associated proteins are targets of autoimmunoreactive IgGs from patients with POTS. Autoimmunity may play a role in the pathogenesis of POTS. ..

Research Grants33

  1. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  2. Redox Regulation of SERCA by Nitric Oxide
    Richard A Cohen; Fiscal Year: 2013
    ..Our proposed studies intend to demonstrate the role for this mechanism in vivo using mouse models of diabetic vascular disease, including a mouse that expresses a mutant SERCA that lacks the key thiol. ..
  3. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  5. Oxidant stress and diabetic endothelial dysfunction
    Ming Hui Zou; Fiscal Year: 2013
    ..abstract_text> ..
  6. ASCORBIC ACID FUNCTION AND METABOLISM
    James M May; Fiscal Year: 2013
    ..Key to his aim is to assess whether diabetes-induced oxidative stress and subsequent endothelial dysfunction is worsened by depletion of ascorbic acid and reversed by its repletion. ..
  7. Peroxynitrite, protein nitration and advanced diabetic neuropathy
    Mark A Yorek; Fiscal Year: 2013
    ..They may also lead to identification of a new biomarker(s) of PDN with diagnostic and prognostic value. ..
  8. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  9. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  10. Reactive nitrogen species and accelerated atherosclerosis in type I diabetes
    Ming Hui Zou; Fiscal Year: 2013
    ....
  11. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  12. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  13. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..