The use of dipeptidyl peptidase 4 inhibitors for the treatment of atherosclerosis

Abstract

Inflammatory processes play a key role in atherogenesis. The drivers of inflammation are endothelial dysfunction, diabetes mellitus, altered lipoprotein metabolism, free radicals, hemodynamic shear stress, hypertension, and other factors. Dipeptidyl peptidase 4 (DPP-4) inhibitors (iDPP-4), in addition to hypoglycemic properties (increase in incretin level and enhancing the expression of their receptors), control the atherogenic factors by regulating the level of blood lipids, blood pressure, attenuation of endothelial dysfunction and oxidative stress, inhibiting inflammatory processes (blocking NF-κB pathway, TLR4 signaling, NLRP3 inflammasome activation and IL-1β secretion by macrophages), stimulation of eNOS activity and NO production, inhibition of endothelin-1, ICAM-1, VCAM-1, E-selectin expression in endothelial cells. IDPP4 reduce the expression of NADPH oxidase subunits Nox2 and p47phox in the aorta, reducing vascular oxidative stress, contributing to the reduction of lipid content and the transformation of macrophages into M2 type in atherosclerotic plaques. M2 polarization during iDPP4-mediated blockade of early atherosclerosis depends on SDF-1α/CXCR4 signaling, which is responsible for increased mobilization into the circulation and chemotactic activity of endothelial progenitor cells involved in endothelial repair. IDPP4 inhibit the progression of atherosclerosis by reducing the levels of MCP-1 and ліганд хемокіну з C-C мотивом-22 in the serum of patients. In addition, iDPP4 reduce the number of monocytes, inhibit TNF-α-induced monocyte migration and macrophage infiltration. Also, iDPP4 suppresse the formation of foam cells, probably by inhibiting the Akt/AMPK pathways of NF-κB and JNK; reduce the expression of LOX-1 and CD36 by inhibiting the activity of protein kinase C, which is involved in the formation of foam cells; demonstrate a significant suppression of migration and proliferation of smooth muscle cells, which leads to a decrease in the intima thickness, play a protective role in restenosis; increase the level of circulating anti-inflammatory factor IL-10, reduce the percentage of macrophages and T-lymphocytes in atherosclerotic plaques.