Nicotinamide Phosphate Transferase (NAMPT) Increases in Plasma in Patients with Acute Coronary Syndromes, and Promotes Macrophages to M2 Polarization

Abstract

Atherosclerosis is an inflammatory disease; monocytes and macrophages play an important role in the progression of this disease. However, the mechanisms are not fully understood yet. Nicotinamide phosphate transferase (NAMPT) is the rate limiting enzyme in the synthesis of NAD, but extracellular NAMPT shows the characteristics of cytokines/adipokines, suggesting that it may be a link between metabolism and inflammation. In this study, we compared the expression levels of the NAMPT/NAD+/Sirt1 signaling pathway as well as NAMPT, CRP and IL-6 in the peripheral blood mononuclear cell (PBMC), and plasma in patients with acute coronary syndromes and healthy subjects, and analyzed their association with macrophage polarization. The relationship between eNAMPT and iNAMPT and the polarization of macrophages was analyzed by NAD+, NAMPT blocker, and neutralizing antibody treatment. The results showed that the expression of the NAMPT/NAD+/Sirt1 signaling pathway was up-regulated in the peripheral blood of patients with ACS. Inhibition of iNAMPT expression can reduce M1 polarization; however, there was no significant effect on eNAMPT secretion and M2 polarization. Neutralizing eNAMPT by neutralizing antibodies can reduce M2 polarization and decrease the expression levels of IL-10, IL-13, IL-4 and IL-1ra. The addition of NAD+ in the cell culture supernatant had no significant effect on the polarization of M1 but increased the M2 polarization and the expression levels of IL-10 and IL-1ra. Our findings suggested that NAMPT is involved in the pathogenesis of atherosclerosis; the increased expression of eNAMPT in ACS patients may play a protective role by the up regulation of the NAMPT/NAD+/Sirt1 signaling pathway.

Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases

“…Notably, NAMPT has been associated with macrophage polarization. Inhibition of intracellular NAMPT was shown to attenuate M1 polarization of human macrophages, whereas neutralizing extracellular NAMPT reduced M2 polarization, as well as expression levels of IL‐1ra, IL‐4, IL‐10 and IL‐13 160 . Moreover, adding NAD + to cultured macrophages increased M2 polarization and the expression levels of IL‐1ra and IL‐10, which are anti‐inflammatory (with no effect on M1).…”

“…In MI, circulating NAMPT levels and intracellular expression in macrophages and monocytes are enhanced 161 . Plasma NAMPT levels are more pronounced in coronary artery diseases compared to healthy controls 160,162 …”

“…Outside the cell eNAMPT, also known as visfatin, acts as a pro‐inflammatory cytokine, promoting development of cardiac hypertrophy and adverse cardiac remodelling with increased activation of mitogen‐activated protein kinases, namely, JNK1, p38 and ERK, 158 although others have proposed that eNAMPT derived from monocytes promoted myocardial adaptation to pressure overload 159 . Serum NAMPT levels correlate with circulating inflammatory markers (IL‐6, CRP and MCP‐1) 160 . In MI, circulating NAMPT levels and intracellular expression in macrophages and monocytes are enhanced 161 .…”

Biomarkers Identification and Therapy Target in Macrophage of Atherosclerosis: Systematic Review

“…Biomarkers related to inflammatory pathways expressed in plaque were reported by six studies [20,[34][35][36][37][38]. Plaque rupture was reported in two studies [39] and [40].…”

Interleukin-4, hemopexin, and lipoprotein-associated phospholipase A2 are significantly increased in patients with unstable carotid plaque

“…In contrast to M1, M2 macrophages secrete antiinflammatory factors, and they can promote angiogenesis and tissue remodeling and repair [47]. In the advanced stage of atherosclerosis, Th2 cytokines are present in the plasma of patients.…”