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 language | English (US) |
|---|---|
| Pages (from-to) | 607-615 |
| Number of pages | 9 |
| Journal | Circulation Research |
| Volume | 114 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 14 2014 |
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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 journal › Article
}
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 -