European journal of pharmacology · 2026
S-nitrosylation of AMP-activated protein kinase beta 1 drives atherosclerotic calcification in diabetes.
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Chen Lin, Zhou Sheng-Nan, Tan Rui-Hang, Zhang Zhen-Shan, Wang Qian-Wen, Wang Xue-Rui, Hu Xiao-Hui, Guo Tao, Li Bin, Wang Shuang-Xi, Liu Fei, Bai Wen-Wu
Аннотация
BACKGROUND: Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation plays a crucial role in multiple cardiovascular diseases. The objective of this study is to examine whether diabetic atherosclerotic calcification is regulated by S-nitrosylation of AMP-activated protein kinase (AMPK), a regulator of VSMC phenotype switching.
METHODS: The atherosclerotic plaque was induced by feeding Apoe-/- mice a high-fat diet. A low dose of streptozotocin (STZ) was used to induce persistent hyperglycemia. Atherosclerotic calcification was assessed using alizarin red staining. S-nitrosylation was evaluated with a biotin-switch method.
RESULTS: In cultured VSMCs, high glucose (HG), but not high osmotic pressure, triggered nitrosative stress, reduced AMPKβ1 protein levels, increased AMPKβ1 S-nitrosylation and ubiquitination, and led to calcification. These effects were abolished by mutating AMPKβ1 at cysteine 173 or 223. Furthermore, mutations of AMPKβ1 at Cys173/223 to alanine restored AMPKβ1 protein levels and suppressed the AKT/Runx2 pathway in HG-treated VSMCs. In vivo, enforced expression of mutated AMPKβ1 (Cys173Ala plus Cys223Ala), but not overexpression of wild-type AMPKβ1, significantly prevented atherosclerotic calcification in diabetic Apoe-/- mice.
CONCLUSION: Nitrosative stress contributes to atherosclerotic calcification in diabetes through AMPKβ S-nitrosylation. In perspective, it is advisable to consider inhibiting AMPKβ S-nitrosylation in diabetic patients with atherosclerosis.
METHODS: The atherosclerotic plaque was induced by feeding Apoe-/- mice a high-fat diet. A low dose of streptozotocin (STZ) was used to induce persistent hyperglycemia. Atherosclerotic calcification was assessed using alizarin red staining. S-nitrosylation was evaluated with a biotin-switch method.
RESULTS: In cultured VSMCs, high glucose (HG), but not high osmotic pressure, triggered nitrosative stress, reduced AMPKβ1 protein levels, increased AMPKβ1 S-nitrosylation and ubiquitination, and led to calcification. These effects were abolished by mutating AMPKβ1 at cysteine 173 or 223. Furthermore, mutations of AMPKβ1 at Cys173/223 to alanine restored AMPKβ1 protein levels and suppressed the AKT/Runx2 pathway in HG-treated VSMCs. In vivo, enforced expression of mutated AMPKβ1 (Cys173Ala plus Cys223Ala), but not overexpression of wild-type AMPKβ1, significantly prevented atherosclerotic calcification in diabetic Apoe-/- mice.
CONCLUSION: Nitrosative stress contributes to atherosclerotic calcification in diabetes through AMPKβ S-nitrosylation. In perspective, it is advisable to consider inhibiting AMPKβ S-nitrosylation in diabetic patients with atherosclerosis.