Article date: July 2017
By: Quanlu Duan, Ping Song, Ye Ding, Ming‐Hui Zou in Volume 174, Issue 13, pages 2140-2151
Background and Purpose
Metformin, one of the most frequently prescribed medications for type 2 diabetes, reportedly exerts BP‐lowering effects in patients with diabetes. However, the effects and underlying mechanisms of metformin on BP in non‐diabetic conditions remain to be determined. The aim of the present study was to determine the effects of metformin on angiotensin II (Ang II) infusion‐induced hypertension in vivo.
Experimental Approach
The effects of metformin on BP were investigated in wild‐type (WT) C57BL/6J mice and in mice lacking AMP‐activated protein kinase α2 (AMPKα2) mice with or without Ang II infusion. Also, the effect of metformin on Ang II‐induced endoplasmic reticulum (ER) stress was explored in cultured human vascular smooth muscle cells (hVSMCs).
Key Results
Metformin markedly reduced BP in Ang II‐infused WT mice but not in AMPKα2‐deficient mice. In cultured hVSMCs, Ang II treatment resulted in inactivation of AMPK, as well as the subsequent induction of spliced X‐box binding protein‐1, phosphorylation of eukaryotic translation initiation factor 2α and expression of glucose‐regulated protein 78 kDa, representing three well‐characterized ER stress biomarkers. Moreover, AMPK activation by metformin ablated Ang II‐induced ER stress in hVSMCs. Mechanistically, metformin‐activated AMPKα2 suppressed ER stress by increasing phospholamban phosphorylation.
Conclusion and Implications
Metformin alleviates Ang II‐triggered hypertension in mice by activating AMPKα2, which mediates phospholamban phosphorylation and inhibits Ang II‐induced ER stress in vascular smooth muscle cells.
DOI: 10.1111/bph.13833
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