title: Nucleoside diphosphate kinase B-activated intermediate conductance potassium channels are critical for neointima formation in mouse carotid arteries.
abstract: OBJECTIVE
  Vascular smooth muscle cells (VSMC) proliferation is a hallmark of atherosclerosis and vascular restenosis. The intermediate conductance Ca(2+)-activated K(+) (SK4) channel is required for pathological VSMC proliferation. In T lymphocytes, nucleoside diphosphate kinase B (NDPKB) has been implicated in SK4 channel activation. We thus investigated the role of NDPKB in the regulation of SK4 currents (ISK4) in proliferating VSMC and neointima formation.
  
  
  RESULTS
  Function and expression of SK4 channels in VSMC from injured mouse carotid arteries were assessed by patch-clamping and real-time polymerase chain reaction. ISK4 was detectable in VSMC from injured but not from uninjured arteries correlating with the occurrence of the proliferative phenotype. Direct application of NDPKB to the membrane of inside-out patches increased ISK4, whereas NDPKB did not alter currents in VSMC obtained from injured vessels of SK4-deficient mice. The NDPKB-induced increase in ISK4 was prevented by protein histidine phosphatase 1, but not an inactive protein histidine phosphatase 1 mutant indicating that ISK4 is regulated via histidine phosphorylation in proliferating VSMC; moreover, genetic NDPKB ablation reduced ISK4 by 50% suggesting a constitutive activation of ISK4 in proliferating VSMC. In line, neointima formation after wire injury of the carotid artery was substantially reduced in mice deficient in SK4 channels or NDPKB.
  
  
  CONCLUSIONS
  NDPKB to SK4 signaling is required for neointima formation. Constitutive activation of SK4 by NDPKB in proliferating VSMC suggests that targeting this interaction via, for example, activation of protein histidine phosphatase 1 may provide clinically meaningful effects in vasculoproliferative diseases such as atherosclerosis and post angioplasty restenosis.
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhou
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Yu-Xi
authors.initials: YX
authors.lastname: Feng
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Katharina
authors.initials: K
authors.lastname: Spiger
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Zhai
authors.initials: Z
authors.lastname: Li
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Michael
authors.initials: M
authors.lastname: Korth
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.).
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: From the 1st Medical Clinic (X.B.-Z., M.B.), Institute of Experimental and Clinical Pharmacology and Toxicology (Y.-X.F., Y.Q., K.S., T.W.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Pharmacology, West German Heart and Vessel Centre, University Duisburg-Essen, Essen, Germany (Q.S., D.D.); Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (R.L., P.R.); Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.K.); Department of Medicine (Z.L., E.Y.S.) and Department of Pharmacology (Z.L., E.Y.S.), Langone Medical Center, New York University; and DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Germany (M.B., T.W.). thomas.wieland@medma.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D054778:NM23 Nucleoside Diphosphate Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058426:Neointima; D015398:Signal Transduction
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D054778:NM23 Nucleoside Diphosphate Kinases; C517941:Nme2 protein, mouse
keywords: KCNN4 protein; KCa3.1 protein; NM23B nucleoside diphosphate kinase; Nme2 protein; SK4 protein; atherosclerosis; neointima formation