Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D₂ Receptor Subtype 1

Abstract

Niacin is a well established drug used to lower cholesterol and prevent cardiovascular disease events. However, niacin also causes cutaneous flushing side effects due to release of the proresolution mediator prostaglandin D 2 (PGD 2 ). Recent randomized clinical trials have demonstrated that addition of niacin with laropiprant [a PGD 2 receptor subtype 1 (DP1) blocker] to statin-based therapies does not significantly decrease the risk of cardiovascular disease events, but increases the risk of serious adverse events. Here, we tested whether, and how, niacin beneficial effects on myocardial ischemia require the activation of the PGD 2 /DP1 axis. Myocardial infarction (MI) was reproduced by ligation of the left anterior descending branch of the coronary artery in mice. We found that niacin increased PGD 2 release in macrophages and shifted macrophages to M2 polarization both in vitro and in vivo by activation of DP1 and accelerated inflammation resolution in zymosan-induced peritonitis in mice. Moreover, niacin treatment facilitated wound healing and improved cardiac function after MI through DP1-mediated M2 bias and timely resolution of inflammation in infarcted hearts. In addition, we found that niacin intake also stimulated M2 polarization of peripheral monocytes in humans. Collectively, niacin promoted cardiac functional recovery after ischemic myocardial infarction through DP1-mediated M2 polarization and timely resolution of inflammation in hearts. These results indicated that DP1 inhibition may attenuate the cardiovascular benefits of niacin.

Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

“…30 Niacin promoted inflammation resolution in a timely manner in the infarcted heart by elevating M2 polarization. 31 Calpastatin overexpression in mice affected the infiltration of the infarcted zone by M2 macrophages and CD4+ T cells, thereby leading to impaired scar healing, elevating the probability of ventricular rupture and decreasing the survival rate of patients with MI. 32 When M1 macrophage-related molecule transcription factor interferon-regulatory factor 5 (IRF5) was downregulated, inflammation resolution and wound healing after MI were promoted and heart failure post-MI was attenuated.…”

Omega-3 fatty acid prevents the development of heart failure by changing fatty acid composition in the heart

“…In cardiomyocytes, because of a low expression of PGD 2 receptors (DP1 and DP2), PGD 2 bound to PGF 2α receptor, and then showed a protective effect against ischemia-reperfusion injury via anti-oxidative effects 55 . In macrophages, the PGD 2 / DP1 axis changed the polarity of macrophage to M2 macrophage, resulted in accelerated resolution of inflammation 56 . In this study, PGD 2 concentration in the heart was higher in vehicle group than in Omega-3 EE group at 2 weeks after operation, while PGF 2α concentration was almost same between two groups (Fig.…”

Niacin ameliorates ulcerative colitis via prostaglandin D 2 ‐mediated D prostanoid receptor 1 activation

“…Recently, we found DP1 deficiency in macrophages led to M1 polarization and delayed resolution in zymosan‐induced peritonitis in mice (Kong et al , , ), and deletion of the DP1 receptor in macrophages (DP1 F/F /LysM Cre ) aggravated DSS‐induced colitis (Fig D–F). We hypothesize that activation of the DP1 receptor in macrophages (i.e., niacin intake) may reduce intestinal inflammation by directing macrophage polarization toward anti‐inflammatory M2‐like cells.…”