Macrophage modulation with dipeptidyl peptidase-4 inhibitors: A new frontier for treating diabetic cardiomyopathy?

Table 1 Molecular mechanisms of macrophage dysfunction in diabetic cardiomyopathy

Mechanism	Consequence	Effect on heart function	Ref.
Increased M1 polarization by hyperglycemia: Activation of nuclear factor-kappaB and mitogen-activated protein kinases pathways	Increased production of pro-inflammatory cytokines (IL-1β, TNF-α) and enhanced generation of reactive oxygen species	Direct cardiomyocyte damage and impaired contractile function	[8,12]
Impaired M2 polarization by hyperglycemia: Downregulation of IL-10 and TGF-β signaling	Reduced production of anti-inflammatory cytokines and impaired clearance of apoptotic cells and tissue repair	Perpetuation of inflammation and delayed wound healing	[7]
NLRP3 inflammasome activation: Triggered by hyperglycemia and damage-associated molecular patterns	Processing and release of pro-inflammatory cytokine IL-1β	Amplification of inflammatory response and aggravated cardiac dysfunction	[12,13,22]
M1 macrophage-mediated cardiomyocyte injury: Release of pro-inflammatory cytokines and reactive oxygen species	Direct damage to cardiomyocytes	Reduced contractility and pump function	[23]
M1 macrophage-promoted fibrosis: Enhanced collagen deposition by fibroblasts	Myocardial stiffening and fibrosis	Impaired relaxation and filling of heart and decreased pump function	[11]
Impaired apoptotic/necrotic cell clearance: Dysfunctional macrophages	Accumulation of cellular debris	Sustained inflammatory response and hindered tissue repair	[10]

TNF: Tumor necrosis factor; IL: Interleukin; TGF: Transforming growth factor.