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Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-a-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

Background: Macrophages produce many inflammation-associated molecules, released by matrix metallo-proteinases (MMPs), such as adhesion molecules as well as cytokines, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (nerve injury-induced protein [Ninj1]), a novel MMP9 substrate, expression and atherosclerosis progression. Methods: Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls as well as athero-prone Apolipoprotein e -deficient ( Apoe -/- ) and wild-type mice. Apoe -/- mice lacking systemic Ninj1 expression ( Ninj1 -/- Apoe -/- ) were generated to assess functional effects of Ninj1. Bone marrow (BM) transplantation was also used to generate low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice that lack Ninj1 specifically in BM-derived cells. Mice were fed a western diet (WD) for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj1 1-56 (ML56) and Ninj1 26-37 (PN12), which mimic the soluble form of Ninj1 (sNinj1). Results: Our in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1 -deficient macrophages promoted pro-inflammatory gene expression by activating mitogenactivated protein kinase (MAPK) and inhibiting the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Whole-body and BM-specific Ninj1 deficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesion through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessed in vitro and in vivo . Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages (CAMs), thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1. Conclusions: Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.

CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in atherosclerotic plaques, and to promote lesion formation. However, the role of CD137 in mediating atherosclerotic plaque stability and the possible underlying molecular and cellular mechanisms are poorly understood. Here, apolipoprotein E-deficient (ApoE(-/-)) and CD137-deficient ApoE(-/-) (ApoE(-/-)CD137(-/-)) mice fed a chow diet for 66 wk were used. CD137 induces plaque instability, which is characterized by increased plaque necrosis, decreased collagen content, decreased vascular smooth muscle cell (VSMC) content, and increased macrophage infiltration. CD137 also increases the infiltration of effector T (Teff) cells into plaque lesion sites, resulting in increased interferon-γ (IFN-γ) expression. Interestingly, Teff-cell-derived IFN-γ inhibits collagen synthesis in atherosclerotic plaques. Furthermore, CD137 activation increases the apoptosis of VSMCs, possibly by decreasing the antiapoptotic regulator, Bcl-2, and subsequently up-regulating cleaved caspase-3. In macrophages, activation of CD137 signaling boosted the oxidized low density lipoprotein-induced expression of matrix metalloproteinase 9 via the p38 mitogen-activated protein kinase and extracellular signal-regulated kinase1/2 signaling pathways. In summary, activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on Teff cells, VSMCs, and macrophages.

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