| First Author | Nystoriak MA | Year | 2014 |
| Journal | Circ Res | Volume | 114 |
| Issue | 4 | Pages | 607-15 |
| PubMed ID | 24323672 | Mgi Jnum | J:223616 |
| Mgi Id | MGI:5659819 | Doi | 10.1161/CIRCRESAHA.114.302168 |
| Citation | Nystoriak MA, et al. (2014) AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. Circ Res 114(4):607-15 |
| abstractText | RATIONALE: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca(2+)-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 beta1 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 beta1 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 beta1 subunits required Ca(2+) influx via voltage-gated L-type Ca(2+) 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 beta1 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. |
