3.1.1 Metformin’s effects on the cardiovascular system
Obesity, dyslipidemia, and insulin resistance are all known risk factors of cardiovascular diseases. Mechanisms that reduce these risk factors underpin the cardiovascular protective effect of metformin. Indeed, AMPK activation by metformin can suppress fatty-acid desaturase (FADS) genes, reducing the circulating levels of lipid metabolites and LDL cholesterol76. In addition, metformin treatment also improves insulin sensitivity and has weight loss effect, which reduce perceived hunger and food intake 77.
The traditional risk factors of cardiovascular diseases such as smoking, high blood pressure, and diabetes cause chronic inflammation and subsequent endothelial dysfunction, both of which play a central role in the development of atherosclerosis. Accumulated data have shown that metformin inhibits vascular inflammation mainly by blockading the PI3K–Akt pathway and suppressing the downstream NF-κB pathway by blockading the PI3K–Akt pathway 78. In diabetic patients, individuals who initiated treatment with metformin have been reported to have lower levels of neutrophil-to-lymphocytes ratio, a marker of systematic inflammation. In non-diabetic patients who have an history of heart failure, metformin treatment has been shown to suppress the circulating pro-inflammatory cytokines, including the aging-associated cytokine CCL1179. Besides, metformin also exerts vascular protective effect by regulating endothelium-derived nitric oxide (NO) produced from nitric oxide synthase (eNOS), two substances that have major roles in maintaining vascular homeostasis and its integrity, including regulating vasodilation and vascular permeability, inhibiting platelet activation, and preventing thrombosis formation. Zou et al shows that when bovine aortic endothelial cells are exposed to clinically relevant amounts of metformin, increased activities of eNOS, NO, and AMPK can be observed while no such effect is observed in AMPK-1 knockout mice, suggesting that AMPK activation by metformin exerts vascular-protective effects 80, 81.