AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus

Matthew A. Nystoriak, Madeline Nieves-Cintrón, Patrick J. Nygren, Simon A. Hinke, C. Blake Nichols, Chao-Yin Chen, Jose L. Puglisi, Leighton T Izu, Donald M Bers, Mark L. Dell'acqua, John D. Scott, Luis Fernando Santana, Manuel F Navedo

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

RATIONALE:: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca-activated K (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown. OBJECTIVE:: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus. METHODS AND RESULTS:: We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. D-glucose-dependent suppression of BKCa channel β1 subunits required Ca influx via voltage-gated L-type Ca channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure. CONCLUSIONS:: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.

Original languageEnglish (US)
Pages (from-to)607-615
Number of pages9
JournalCirculation Research
Volume114
Issue number4
DOIs
StatePublished - Feb 14 2014

Fingerprint

Calcium-Activated Potassium Channels
Hyperglycemia
Protein Kinases
Blood Vessels
Diabetes Mellitus
Calcineurin
NFATC Transcription Factors
High Fat Diet
Vasoconstriction
Down-Regulation
Staphylococcal Protein A
Constriction
Muscle Cells
Arterial Pressure
Arteries
Glucose

Keywords

  • calcineurin
  • hyperglycemia
  • hypertension
  • ion channels
  • potassium channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. / Nystoriak, Matthew A.; Nieves-Cintrón, Madeline; Nygren, Patrick J.; Hinke, Simon A.; Nichols, C. Blake; Chen, Chao-Yin; Puglisi, Jose L.; Izu, Leighton T; Bers, Donald M; Dell'acqua, Mark L.; Scott, John D.; Santana, Luis Fernando; Navedo, Manuel F.

In: Circulation Research, Vol. 114, No. 4, 14.02.2014, p. 607-615.

Research output: Contribution to journalArticle

Nystoriak, Matthew A. ; Nieves-Cintrón, Madeline ; Nygren, Patrick J. ; Hinke, Simon A. ; Nichols, C. Blake ; Chen, Chao-Yin ; Puglisi, Jose L. ; Izu, Leighton T ; Bers, Donald M ; Dell'acqua, Mark L. ; Scott, John D. ; Santana, Luis Fernando ; Navedo, Manuel F. / AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. In: Circulation Research. 2014 ; Vol. 114, No. 4. pp. 607-615.
@article{b223b79f261d4c62b8d5510e05c7e9ee,
title = "AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus",
abstract = "RATIONALE:: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca-activated K (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown. OBJECTIVE:: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus. METHODS AND RESULTS:: We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. D-glucose-dependent suppression of BKCa channel β1 subunits required Ca influx via voltage-gated L-type Ca channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure. CONCLUSIONS:: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.",
keywords = "calcineurin, hyperglycemia, hypertension, ion channels, potassium channels",
author = "Nystoriak, {Matthew A.} and Madeline Nieves-Cintr{\'o}n and Nygren, {Patrick J.} and Hinke, {Simon A.} and Nichols, {C. Blake} and Chao-Yin Chen and Puglisi, {Jose L.} and Izu, {Leighton T} and Bers, {Donald M} and Dell'acqua, {Mark L.} and Scott, {John D.} and Santana, {Luis Fernando} and Navedo, {Manuel F}",
year = "2014",
month = "2",
day = "14",
doi = "10.1161/CIRCRESAHA.114.302168",
language = "English (US)",
volume = "114",
pages = "607--615",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus

AU - Nystoriak, Matthew A.

AU - Nieves-Cintrón, Madeline

AU - Nygren, Patrick J.

AU - Hinke, Simon A.

AU - Nichols, C. Blake

AU - Chen, Chao-Yin

AU - Puglisi, Jose L.

AU - Izu, Leighton T

AU - Bers, Donald M

AU - Dell'acqua, Mark L.

AU - Scott, John D.

AU - Santana, Luis Fernando

AU - Navedo, Manuel F

PY - 2014/2/14

Y1 - 2014/2/14

N2 - RATIONALE:: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca-activated K (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown. OBJECTIVE:: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus. METHODS AND RESULTS:: We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. D-glucose-dependent suppression of BKCa channel β1 subunits required Ca influx via voltage-gated L-type Ca channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure. CONCLUSIONS:: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.

AB - RATIONALE:: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca-activated K (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown. OBJECTIVE:: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus. METHODS AND RESULTS:: We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. D-glucose-dependent suppression of BKCa channel β1 subunits required Ca influx via voltage-gated L-type Ca channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure. CONCLUSIONS:: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.

KW - calcineurin

KW - hyperglycemia

KW - hypertension

KW - ion channels

KW - potassium channels

UR - http://www.scopus.com/inward/record.url?scp=84894480266&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894480266&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.114.302168

DO - 10.1161/CIRCRESAHA.114.302168

M3 - Article

C2 - 24323672

AN - SCOPUS:84894480266

VL - 114

SP - 607

EP - 615

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 4

ER -