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  2. AGEs impair Kv channel-mediated vasodilation of coronary arteries by activating the NF-κB signaling pathway in ZDF rats

AGEs impair Kv channel-mediated vasodilation of coronary arteries by activating the NF-κB signaling pathway in ZDF rats

  • Biomed Pharmacother. 2019 Dec;120:109527. doi: 10.1016/j.biopha.2019.109527.
Qingbo Liu 1 Bing Hua 1 Wen Su 1 Beibing Di 1 Shandong Yu 1 Side Gao 1 Huirong Liu 2 Xueqiao Zhao 3 Weiping Li 4 Hongwei Li 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China.
  • 2 School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Disease, Beijing 100069, PR China.
  • 3 Clinical Atherosclerosis Research Lab, Division of Cardiology, University of Washington, Seattle, WA, USA.
  • 4 Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China; Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Disease, Beijing 100069, PR China. Electronic address: xueer09@163.com.
  • 5 Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China; Department of Internal Medicine, Medical Health Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China; Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Disease, Beijing 100069, PR China. Electronic address: lhw19656@sina.com.
Abstract

Excessive formation of advanced glycation end products (AGEs) impairs voltage-gated potassium (Kv) channels in rat coronary artery smooth muscle cells (CSMCs), resulting in weakened Kv-mediated coronary vasodilation. We hypothesized that induction of the nuclear factor-κB (NF-κB) signaling pathway by AGEs plays a significant role in the regulation of Kv channel-mediated vasodilation in Zucker diabetic fatty (ZDF) rats. Assays of mRNA transcripts, protein expression, and intracellular localization as well as patch-clamp experiments in cultured CSMCs revealed that AGEs significantly induced activation of the NF-κB signaling pathway, reduced Kv1.2/1.5 expression, and inhibited Kv currents. In addition, silencing of the receptor for AGEs (RAGE) or p65 with siRNA and treatment with alagrebrium (ALA) or pyrrolidine dithiocarbamate (PDTC) alleviated the AGE-induced impairment of Kv channels in CSMCs. Compared with Zucker lean (ZL) rats, the amount of AGEs, RAGE protein expression, and NF-κB activity in coronary arteries were higher in ZDF rats; whereas Kv1.2/1.5 expression was significantly lower in ZDF rats. Reduced Kv1.2/1.5 expression in coronary arteries and impaired Kv-mediated coronary relaxation tested by wire myography in ZDF rats were markedly improved by treatment with aminoguanidine (AG), ALA, or PDTC. These effects were accompanied by diminished NF-κB activity, inflammation, and oxidative stress. Taken together, these results indicate that an increased interaction between AGEs and RAGE in diabetic rats leads to impaired Kv channel-mediated coronary vasodilation. Moreover, activation of the NF-κB signaling pathway and a subsequent increase of inflammation and oxidative stress may play an important role in AGE-induced impairment of coronary vasodilation in diabetes.

Keywords

Advanced glycation end products; Coronary vasodilation; NF-κB signaling pathway; Voltage-gated potassium channels; Zucker diabetic fatty rats.

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