Prostaglandin E2 confers protection against diabetic coronary atherosclerosis by stimulating M2 macrophage polarization via the activation of the CREB/BDNF/TrkB signaling pathway

Abstract

It has been documented that M2 macrophage polarization plays a suppressive role in atherosclerosis in diabetes mellitus (DM). In addition, prostaglandin E2 (PGE2) is implicated in the development of M2 macrophage polarization. Therefore, the study aimed to investigate the specific mechanism of PGE2 in M2 macrophage polarization in diabetic coronary atherosclerosis (DMAS). Initially, clinical samples were obtained and DMAS mouse model was established. The expression of BDNF was determined, and M1 and M2 macrophage polarizations were evaluated. Then, the levels of BDNF and PGE2 were modified in DMAS mice and the serum indicator, atherosclerotic plaque, lipid uptake by PBMCs, as well as M1 and M2 macrophage polarization were determined. Macrophages were isolated and the effects of PGE2 and the CREB/BDNF/TrkB signaling pathway on M2 macrophage polarization were explored. BDNF was downregulated and macrophages were differentiated into M1 in DMAS patients and mice. BDNF and PGE2 were observed to promote M2 macrophage polarization, where atherosclerotic plaque and lipid uptake by PBMCs were reduced, and DMAS was alleviated in mice. Overexpression of BDNF activated the CREB/BDNF/TrkB signaling pathway and stimulated M2 macrophage polarization in macrophages. PGE2 stimulated M2 macrophage polarization by inducing KLF4 via the activation of the CREB/BDNF/TrkB signaling pathway. This study demonstrates that PGE2 promotes M2 macrophage polarization by activating the CREB/BDNF/TrkB signaling pathway, thus alleviating DMAS.

HOXA5 induces M2 macrophage polarization to attenuate carotid atherosclerosis by activating MED1

“…Some evidences describe that atherosclerotic progression is regulated by recruitment of macrophages, reflected in increased lipid accumulation, and thickened arterial wall 31 . Previous studies showed that blocking macrophage polarization toward an M1 status likely reduced atherosclerotic plaque burden and intimal area in atherosclerosis, 24 whereas the stimulation of M2 macrophage polarization protected against atherosclerotic lesions 32 . In the present study, we observed that HOXA5 inhibited neointimal hyperplasia and plaque formation in CAS mice.…”

Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

“…However, PGE 2 has also been linked with beneficial effects on the islet phenotype. For example, PGE 2 promotes M2 macrophage polarization, preventing pro-inflammatory cytokine production and promoting β-cell survival [5]. Therefore, what physiological changes might transition islet EP3 signaling from protective to detrimental remain unknown.…”

Exploiting oxidized lipids and the lipid‐binding GPCRs against cardiometabolic diseases

“…This mechanism is known to underlie the protective effect of PGE 2 against atherosclerosis. Bi et al (2020) have demonstrated that PGE 2 ameliorates diabetes-related atherosclerosis through the stimulation of macrophage polarization through the activation of the transcription factor Kruppel-like factor 4 (KLF4). Consistent with this finding, the pro-atherogenic effect of the COX-2 inhibitor celecoxib was recently associated with its suppressive effect on PGE 2 and NO levels, concomitantly with the induction of LTB 4 and LTs (Pang et al, 2019).…”