Therapeutic strategies targeting mechanisms of macrophages in diabetic heart disease

Figures

• 

  Fig. 1. A schematic representation of macrophage polarization. Monocytes can be differentiated into M0 macrophages in response to M-CSF stimulation. M0 macrophages can be polarized into M1 macrophages in response to LPS or Th1 cytokines (INF-γ, TNF-α). M0 macrophages are polarized into M2 macrophages in response to Th2 cytokines (IL-4, IL-13). Depending on the stimuli, M2 macrophages are subdivided into M2a, M2b, M2c, and M2d macrophages. Abbreviations: M-CSF: macrophage colony-stimulating factor, INF-γ: interferon-γ, TNF-α: tumor necrosis factor-α, LPS: lipopolysaccharide, IL: interleukin, TGF-β: transforming growth factor-β, TLR: toll-like receptor

• 

  Fig. 2. Schematic diagram of the mechanisms involved in the development of DHD by macrophages. The hyperglycemic environment in diabetic patients induces CM injury, and necrotic CMs activate mast cells by releasing DAMPs, which induce the secretion of TNF-α and IL-1β, leading to the activation of ECs. Activated ECs induce monocytes to differentiate into CCR2+ macrophages and CCR2-macrophages; the former create an inflammatory environment and remove necrotic tissue, while the latter release IL-10 and TGF-β1, which activate fibroblasts to differentiate into myofibroblasts and produce ECM and collagen for tissue repair. The hyperglycemic environment also directly activates ECs, which secrete cytokines and chemokines that induce macrophage polarization to the M1 phenotype. In turn, M1 macrophages secrete inflammatory factors that promote cardiac inflammatory responses and insulin resistance. In addition, a hyperglycemic environment leads to increased production of AGEs, and the overproduction of AGEs promotes ROS production. The hyperglycemic environment can also act on HMGB1, gradually activating their downstream reactions, leading to increased ROS generation, and exacerbating oxidative…

• 

  Fig. 3. Summary schematic. Inflammation, myocardial fibrosis, insulin resistance, and oxidative stress are the four core mechanisms leading to DHD, and macrophages may play an essential role in these mechanisms. Five types of drugs—SGLT2is, GLP1RAs, metformin, RAASis, and β2ARAs—may have therapeutic potential by regulating macrophages. MiRNAs, which also regulate macrophages, may be involved in the pathogenesis of DHD and may also be potential targets for the treatment of DHD. In addition, melatonin is a promising research direction for treating DHD. Abbreviations: ACE: angiotensin-converting enzyme, AMPK: adenosine monophosphate-activated protein kinase, BW: body weight, BP: blood pressure, CV: cardiovascular, IL: interleukin, MCP-1: monocyte chemoattractant protein-1, NF-κB: nuclear factor kappa-B, ROS: reactive oxygen species, TLR: toll-like receptor, TNF-α: tumor necrosis factor-α