AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus.
Enviado por Manuel F Navedo el
Título | AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Autores | Nystoriak, MA, Nieves-Cintrón, M, Nygren, PJ, Hinke, SA, C Nichols, B, Chen, C-Y, Puglisi, JL, Izu, LT, Bers, DM, Dell'acqua, ML, Scott, JD, Santana, LF, Navedo, MF |
Journal | Circ Res |
Volume | 114 |
Issue | 4 |
Pagination | 607-15 |
Date Published | 2014 Feb 14 |
ISSN | 1524-4571 |
Palabras clave | A Kinase Anchor Proteins, Animals, Diabetes Mellitus, Experimental, Dietary Fats, Gene Knock-In Techniques, Hyperglycemia, Hypertension, Large-Conductance Calcium-Activated Potassium Channel beta Subunits, Large-Conductance Calcium-Activated Potassium Channels, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Muscle, Smooth, Vascular, NFATC Transcription Factors, Peptides, Signal Transduction, Toxins, Biological, Vasoconstriction |
Abstract | 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 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(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 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. |
DOI | 10.1161/CIRCRESAHA.114.302168 |
Alternate Journal | Circ. Res. |
PubMed ID | 24323672 |
PubMed Central ID | PMC3954117 |
Grant List | HL07828 / HL / NHLBI NIH HHS / United States HL085686 / HL / NHLBI NIH HHS / United States HL085870 / HL / NHLBI NIH HHS / United States HL086350-05 / HL / NHLBI NIH HHS / United States HL098200 / HL / NHLBI NIH HHS / United States MH080291 / MH / NIMH NIH HHS / United States NS040701 / NS / NINDS NIH HHS / United States NS048154 / NS / NINDS NIH HHS / United States R01 HL030077 / HL / NHLBI NIH HHS / United States R01 HL085870 / HL / NHLBI NIH HHS / United States R01 HL098200 / HL / NHLBI NIH HHS / United States T32 HL007828 / HL / NHLBI NIH HHS / United States T32 HL086350 / HL / NHLBI NIH HHS / United States |