Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function.

Mingying Deng,Aizong Shen,Liqin Tang,Suowen Xu,Xiaojun Feng,Dan Su,Peter J Little

doi:10.3389/fphar.2020.00635

Abstract

Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD.

Highlights

Metformin is a biguanide that is available from extracts of folk medicinal plant Galega officinalis leaves (Palmer and Strippoli, 2018; Prattichizzo et al, 2018)
We focus on the effects of metformin on vascular function by regulating Vascular smooth muscle cells (VSMCs) function, including vasoconstriction/Pulmonary Arterial Hypertension (PAH), intimal thickening, vascular calcification, and inflammation
We focus on the role of metformin in cardiovascular diseases (CVD), including AS and PAH, and clarify that metformin plays a beneficial role in the above CVD by improving the function of VSMCs

Summary

INTRODUCTION

Metformin is a biguanide that is available from extracts of folk medicinal plant Galega officinalis leaves (Palmer and Strippoli, 2018; Prattichizzo et al, 2018). In VSMCs and pancreatic beta cells, phenformin but not metformin inhibits many KATP variants (Aziz et al, 2010) These studies suggest that metformin relaxes vascular smooth muscle mechanisms: enhances insulin sensitivity, inhibits methylglyoxal activation of the renin angiotensin system, and inhibits multiple inducers (including PDGF or ANG II)stimulated [Ca2+]i rise, as well as inhibits PE-induced [K+]i rise. It is precisely because of the antihypertensive effect of metformin by inhibiting [Ca2+]i and/or [K+]i, so metformin and bezafibrate have no significant effect on Ca2+ current or high K+ induced contraction (Nakamura et al, 1998). The indirect sympathomimetic effect can be amplified by a monoamine oxidase inhibitor (such as promethazine) and blocked by a NE-carrier inhibitor (such as desipramine), so that metformin has beneficial vasodilatation in diabetic patients with hypertension may be affected by commonly used antidepressants similar to promethazine and desipramine (Lee and Peuler, 2001)

Vascular Calcification

Intimal Thickening

Inflammatory Response

MOLECULAR TARGETS OF METFORMIN

CONCLUSION AND PERSPECTIVES