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) |
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Pages (from-to) | 607-615 |
Number of pages | 9 |
Journal | Circulation Research |
Volume | 114 |
Issue number | 4 |
DOIs | |
State | Published - Feb 14 2014 |
Keywords
- calcineurin
- hyperglycemia
- hypertension
- ion channels
- potassium channels
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine