Metformin prevents vascular damage in hypertension through the AMPK/ER stress pathway

Area of Science:

• Cardiovascular Research
• Pharmacology
• Endocrinology

Background:

• Metformin is a primary antidiabetic medication.
• Its beneficial effects in non-diabetic conditions, particularly cardiovascular diseases, require further investigation.
• Angiotensin II (Ang II) infusion is a model for inducing hypertension and cardiovascular complications.

Purpose of the Study:

• To investigate the therapeutic potential of metformin in mitigating Ang II-induced hypertension and associated cardiovascular dysfunction.
• To explore the role of endoplasmic reticulum (ER) stress in Ang II-induced vascular damage and the impact of metformin on this pathway.

Main Methods:

• Mice were infused with Ang II (400 ng/kg/min) for two weeks, with or without concurrent metformin administration.
• Vascular function, blood pressure, and markers of ER stress were assessed.
• Specific molecular pathways, including AMPK and eNOS phosphorylation, were analyzed.
• Tunicamycin was used to induce ER stress in control mice to further elucidate metformin's mechanism.

Main Results:

• Ang II infusion led to increased blood pressure and elevated vascular ER stress markers.
• Metformin treatment significantly blunted these Ang II-induced effects.
• Hypertension-associated reductions in phosphorylated AMPK, eNOS, and endothelium-dependent relaxation (EDR) were restored by metformin.
• Metformin reversed tunicamycin-induced ER stress, improved vascular function, and normalized molecular markers without affecting blood pressure.

Conclusions:

• Metformin effectively improves vascular function and mitigates hypertension in a preclinical model.
• Inhibition of ER stress is a key mechanism by which metformin exerts its protective cardiovascular effects.
• Metformin presents a potential therapeutic strategy for cardiovascular diseases in hypertension, independent of its glucose-lowering properties.