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.