Adropin Contributes to Anti-Atherosclerosis by Suppressing Monocyte-Endothelial Cell Adhesion and Smooth Muscle Cell Proliferation

Abstract

Adropin, a peptide hormone expressed in liver and brain, is known to improve insulin resistance and endothelial dysfunction. Serum levels of adropin are negatively associated with the severity of coronary artery disease. However, it remains unknown whether adropin could modulate atherogenesis. We assessed the effects of adropin on inflammatory molecule expression and human THP1 monocyte adhesion in human umbilical vein endothelial cells (HUVECs), foam cell formation in THP1 monocyte-derived macrophages, and the migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro and atherogenesis in Apoe−/− mice in vivo. Adropin was expressed in THP1 monocytes, their derived macrophages, HASMCs, and HUVECs. Adropin suppressed tumor necrosis factor α-induced THP1 monocyte adhesion to HUVECs, which was associated with vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 downregulation in HUVECs. Adropin shifted the phenotype to anti-inflammatory M2 rather than pro-inflammatory M1 via peroxisome proliferator-activated receptor γ upregulation during monocyte differentiation into macrophages. Adropin had no significant effects on oxidized low-density lipoprotein-induced foam cell formation in macrophages. In HASMCs, adropin suppressed the migration and proliferation without inducing apoptosis via ERK1/2 and Bax downregulation and phosphoinositide 3-kinase/Akt/Bcl2 upregulation. Chronic administration of adropin to Apoe−/− mice attenuated the development of atherosclerotic lesions in the aorta, with reduced the intra-plaque monocyte/macrophage infiltration and smooth muscle cell content. Thus, adropin could serve as a novel therapeutic target in atherosclerosis and related diseases.

Adropin as A Fat-Burning Hormone with Multiple Functions—Review of a Decade of Research

“…Of note, beneficial effects of adropin detected in vitro were confirmed by an in vivo study showing that adropin stimulates neovascularization via activation of eNOS kinase [46]. Concordantly, another study revealed that adropin has the ability to suppress THP1 monocyte adhesion to HUVEC cells induced by TNFα, suggesting an anti-inflammatory potential of adropin [47]. Moreover, in apolipoprotein E (Apoe) deficient mice (animal model of atherosclerosis [48]) synthetic adropin led to attenuation of atherosclerotic lesions and monocyte/macrophage infiltration in the aorta [47].…”

“…Concordantly, another study revealed that adropin has the ability to suppress THP1 monocyte adhesion to HUVEC cells induced by TNFα, suggesting an anti-inflammatory potential of adropin [47]. Moreover, in apolipoprotein E (Apoe) deficient mice (animal model of atherosclerosis [48]) synthetic adropin led to attenuation of atherosclerotic lesions and monocyte/macrophage infiltration in the aorta [47]. In the context of the cardiovascular system, adropin may modulate the patency of the blood-brain barrier [49].…”

A Review of Adropin as the Medium of Dialogue between Energy Regulation and Immune Regulation

“…Therefore, activation of PPAR-γ may reduce macrophage infiltration and inflammation of adipose tissues. The study demonstrated that adropin regulates the anti-inflammatory or proinflammatory phenotypes of macrophages by up-regulating the expression of PPAR-γ [24]. Although, in current research, the reason for the tissue-specific effects of adropin on PPAR-γ expression is often unclear, PPAR-γ may be an important target for adropin to exert anti-inflammatory effects (Figure 2).…”

“…On the one hand, as an endogenous vasodilator, NO plays a substantial role in maintaining the homeostasis of endothelial cells [31]; on the other hand, NO can exert immunomodulatory influences in inhibiting adhesion of monocytes and leukocytes to the endothelia [32]. Sato et al [24] demonstrated that adropin can inhibit TNF-α-induced adhesion of THP1 monocytes to endothelial cells in the process of atherosclerosis. With impeding monocyte-endothelial cell interactions, it can inhibit the inflammatory response of endothelial cells and monocytes/macrophages.…”

“…Hyperhomocysteinemia activates c-Jun N-terminal kinase by inducing endoplasmic reticulum stress, which can stimulate the production of proinflammatory cytokines and promote macrophage infiltration, thereby promoting insulin resistance [34]. (2) Inflammatory cytokines: studies conducted by Sato et al [24] showed that adropin could reduce the expressions of TNF-α and IL-6 at the mRNA level by regulating the expression of iNOS, thereby exerting anti-inflammatory effects on the atherosclerosis. (3) CD36: CD36, which can be downregulated by adropin, is a multi-ligand and multifunctional inflammatory receptor that induces inflammatory responses through activation of various ligands and cellular responses; for example, the interaction with fibrillar β-amyloid (fAβ)/integrin can induce an inflammatory response by increasing expressions of proinflammatory cytokines and chemokines; CD36 receptor for oxidized low-density lipoprotein (oxLDL) can alter cytoskeletal dynamics, enhance macrophage spreading, and inhibit migration.…”