AKAP150 Contributes to Enhanced Vascular Tone by Facilitating Large- Conductance Ca2+- Activated K plus Channel Remodeling in Hyperglycemia and Diabetes Mellitus

作者：Nystoriak Matthew A; Nieves Cintron 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 F; Navedo Manuel F^*

来源：Circulation Research, 2014, 114(4): 607-615.

DOI：10.1161/CIRCRESAHA.114.302168

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

Rationale: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca2+-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 1 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 1 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 1 subunits required Ca2+ influx via voltage-gated L-type Ca2+ 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 1 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.

• 出版日期2014-2-14