Metformin, Macrophage Dysfunction and Atherosclerosis

Abstract

Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging.

High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases

“…A strong correlation between matrix metalloproteinase 9 (MMP-9) and HMGB1 levels, which was associated with poor outcomes, has been reported in ischemic stroke patients [ 75 ]. Various studies have demonstrated that blocking or modulating HMGB1 by compounds such as statins or by RNA interference provide neuroprotective effects against ischemic stroke [ 76 , 77 ]. Recently, HMGB1 has been studied for its role in epilepsy.…”

Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

“…In renal tubular epithelial cells, metformin inhibited senescence and alleviated diabetic nephropathy through the muscleblind-like 1 /miR-130a-3p/STAT3 signaling pathway 175 . In addition, metformin repressed endothelial senescence by activating the activity of Sirt1 176 , and inhibited macrophage senescence and SASP by down-regulating NLRC4 phosphorylation 177 . Śmieszek A et al 178 found that metformin suppressed SASP and senescence in ex vivo cultures of murine olfactory ensheathing cell via down-regulation of NF-κB signaling.…”

Post-Translational Modification of HMGB1 Disulfide Bonds in Stimulating and Inhibiting Inflammation

“…Nuclear hyperacetylation is also accomplished via increased histone-acetylase (HAT) activity as well as decreased histone-deacetylase (HDAC) activity [ 7 , 8 , 9 ]. Several agents including metformin, resveratrol, and curcumin (which all enhance sirtuin 1 (SIRT1) deacetylase activity) decrease extracellular HMGB1 release and reduce HMGB1-dependent inflammation [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Decreased activity of SIRT1, a nicotinamide adenine dinucleotide-dependent HDAC, occurs in aging and senescence, suggesting a role for HMGB1 in the inflammation associated with aging (“inflammageing”) [ 19 , 20 , 21 ].…”