Advanced glycation end products impair coronary artery BK channels via AMPK/Akt/FBXO32 signaling pathway

Author:

Li Xiao-Yan1,Qian Ling-Ling1,Wu Ying1,Zhang Yu-Min1,Dang Shi-Peng1,Liu Xiao-Yu1,Tang Xu1,Lu Cun-yu1,Wang Ru-Xing1ORCID

Affiliation:

1. Department of Cardiology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China

Abstract

Background: Advanced glycation end products (AGEs) impair vascular physiology in Diabetes mellitus (DM). However, the underlying mechanisms remain unclear. Vascular large conductance calcium-activated potassium (BK) channels play important roles in coronary arterial function. Purpose: Our study aimed to investigate the regulatory role of AGEs in BK channels. Research Design: Using gavage of vehicle (V, normal saline) or aminoguanidine (A) for 8 weeks, normal and diabetic rats were divided into four groups: C+V group, DM+V group, C+A group, and DM+A group. Study Sample: Coronary arteries from different groups of rats and human coronary smooth muscle cells were used in this study. Data Collection and Analysis: Data were presented as mean ± SEM (standard error of mean). Student's t-test was used to compare data between two groups. One-way ANOVA with post-hoc LSD analysis was used to compare data between multiple groups. Results: Compared to the C+V group, vascular contraction induced by iberiotoxin (IBTX), a BK channel inhibitor, was impaired, and BK channel densities decreased in the DM+V group. However, aminoguanidine administration reduced the impairment. Protein expression of BK-β1, phosphorylation of adenosine 5’-monophosphate-activated protein kinase (AMPK), and protein kinase B (PKB or Akt) were down-regulated, while F-box protein 32 (FBXO32) expression increased in the DM+V group and in high glucose (HG) cultured human coronary smooth muscle cells. Treatment with aminoguanidine in vitro and in vivo could reverse the above protein expression. The effect of aminoguanidine on the improvement of BK channel function by inhibiting the generation of AGEs was reversed by adding MK2206 (Akt inhibitor) or Compound C (AMPK inhibitor) in HG conditions in vitro. Conclusions: AGEs aggravate BK channel dysfunction via the AMPK/Akt/FBXO32 signaling pathway.

Funder

National Natural Science Foundation of China

Research Foundation from Wuxi Health Commission for the Youth

Top Talent Support Program for Young and Middle-aged People of Wuxi Health Committee

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Endocrinology, Diabetes and Metabolism,Internal Medicine

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