Atheroprotective properties of human Omentin-1 in experimental atherosclerosis

This editorial refers to ‘Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice’, by M. Hiramatsu-Ito et al., pp. 107–117. This editorial refers to ‘Counteractive effects of omentin-1 against atherogenesis’, by K. Watanabe et al., pp. 118–128. It has been clearly established that adipocytes are not merely involved in energy storage, but function as an endocrine organ involved in different metabolic and inflammatory responses. For this reason, the role of adipose tissue in cardiovascular and metabolic diseases has gained increasing interest. In mammals, two types of adipose tissue can be distinguished, white and brown fat. Brown fat is more abundant in newborns and is relevant for the generation of heat. Two different types of white adipose tissue can be distinguished, subcutaneous and visceral fat, of which the latter is metabolically active. Under healthy conditions, visceral adipose tissue has balanced, non-metabolic, and non-inflammatory properties. In diseased state, as seen in obese or cardiovascular patients, the white adipose tissue reveals a shift towards a disbalanced metabolic and pro-inflammatory state.1 Diseased fat can exert systemic effects resulting in insulin resistance and metabolic syndrome, which both attribute to the onset of cardiovascular disease (CVD).2 In addition, epicardial and peri-adventitial adipose deposits can also focally influence atherosclerotic lesion formation, progression, and stability.3 Adipose tissue releases a plethora of bioactive factors termed adipokines, which consist of enzymes, hormones, growth factors, chemokines, and cytokines. Under healthy condition, white adipose tissue mainly produces anti-inflammatory adipokines, like adiponectin. However, it has been established that diseased adipose tissue, as seen in obesity, can switch to a pro-inflammatory state with high expression of leptin, CCL2, interleukin-6, and TNFα. In the context of CVD, leptin and adiponectin are best studied. Obviously, adipokines are produced in vast amounts by adipocytes but many are also generated by other cell types. With their receptors being expressed in several organs and cell types, many adipokines have a wide range of pleiotropic effects. Omentin-1 is a newly identified adipokine, also referred to as Intellectin-1, that is highly expressed in visceral fat and binds to currently unidentified receptor(s).4,5 Similar to adiponectin, Omentin-1 has been negatively associated with insulin resistance, diabetes, obesity, and metabolic syndrome. Low Omentin-1 levels have been associated with arterial stiffness and the presence of atherosclerosis in type II diabetes patients6 and circulating levels of Omentin-1 have been related to lipoprotein metabolism.7 Besides, low Omentin-1 levels have been associated with the presence and severity of atherosclerosis, where stable angina pectoris patients have higher omentin-1 levels compared with unstable patients. Previously, it has been reported that Omentin-1 can suppress inflammatory responses and apoptosis in endothelial cells8–10 and inhibits vascular smooth muscle cell proliferation and neointima formation.11 These observations clearly suggest that omentin-1 is an interesting causal player in atherosclerosis and plaque stability. Two independent research groups Watanabe et al.12 and Hiramatsu-Ito et al.13 have further investigated the role of Omentin-1 in atherosclerosis. Watanabe et al. show that Omentin-1 is expressed, in atherosclerosis-associated cell types, albeit less abundant compared with adipocytes, such as endothelial cells, vascular smooth muscle cells, and macrophages. Despite ∼80–85% homology between human and mouse Omentin-1,5 expression profiles differ between these species. While in humans Omentin-1 is highly expressed in visceral fat, in mice it is not expressed in fat tissue.14 Therefore, in order to study the effect of Omentin-1 as an adipokine in atherosclerotic lesion formation and progression, mice were exposed to human Omentin-1 either by long-term infusion (Watanabe et al.12) or by gain-of-function genetic manipulation (Hiramatsu-Ito et al.13). In both studies, exposure to Omentin-1 attenuated atherosclerotic lesion formation and progression in the aorta and aortic root valve area of ApoE-deficient mice. The reduction in lesion formation was accompanied by an overall reduced inflammatory phenotype with decreased mRNA expression of adhesion molecules, cyto-/chemokines and reduced monocyte/macrophage infiltration, vascular smooth muscle cell, and collagen content. As atherosclerosis is a lipid-driven inflammatory disorder, the effects of Omentin-1 on foam cell formation and inflammation were determined. Exposure to physiological concentrations of Omentin-1 inhibited oxLDL-induced foam cell formation that was accompanied by decreased expression of scavenger receptors CD36 and SR-A. Omentin-1 does not affect monocyte differentiation into macrophages but does appear to influence macrophage polarization towards an anti-inflammatory M2 phenotype. In addition, Ometin-1 potently inhibits LPS-induced inflammation in macrophages with evidently reduced NFκB activation, TNFα and IL-6 production. Both studies further substantiate the anti-atherogenic effect of Omentin-1 (depicted in Figure 1). Specifically the reported effects on foam cell formation and polarization of macrophages towards a more anti-inflammatory phenotype warrant further investigation to provide more insight towards therapeutic targeting. However, it must be noted that the study design and the subsequent outcomes may point to different modes of actions of Omentin-1. For instance, infusion of 5 μg/kg/h (≈3500 ng/day) of Omentin-1 by using an osmotic minipump did not result in elevated plasma concentrations of Omentin-1 (≈1 ng/mL), but did significantly reduce total cholesterol levels in ApoE-deficient mice on a high cholesterol diet. This may imply that most of the infused Omentin-1 is accumulated in the liver, where it can directly influence cholesterol metabolism. One cannot rule out that the observed reduced atherosclerotic lesion formation is an indirect consequence of reduced cholesterol levels that is caused by increased hepatic Omentin-1 levels. On the other hand, genetic overexpression, specifically in adipocytes and macrophages, did result in robust elevation of circulating Omentin-1 (≈1000 ng/mL), while total cholesterol levels remained unchanged in ApoE-deficient mice on chow diet. The latter result suggests that the observed effects on atherosclerotic lesion formation are indeed independent of circulating cholesterol and that Omentin-1 directly affects plaque-associated cell types. Whether adipocyte-derived Omentin-1 or macrophage-derived Omentin-1 is most crucial for these effects remains to be established. Effects of Omentin-1 on atherosclerosis-associated cell types. Omentin-1 inhibits oxLDL-induced foam cell formation via down-regulation of scavenger receptors. Macrophage differentiation is not affected, while Omentin-1 can skew macrophage polarization towards M2 phenotype and inhibits the release of pro-atherogenic factors. Migration and proliferation of vascular smooth muscle cells is controlled by Omentin-1, while its effect on matrix homeostasis is not completely clear. Despite earlier reports on higher Omentin-1 levels in stable angina pectoris patients compared with patients with unstable coronary syndromes, the involvement of Omentin-1 in human atherosclerotic plaque progression and stability remains to be clarified. The observed diverse effects of Omentin-1 on plaque volume and characteristics suggest both direct and indirect involvement of Omentin-1 in the complex interplay of local inflammation and extracellular matrix turnover. The studies reported in this issue of Cardiovascular Research warrant further in depth examination of Omentin-1 in human vascular occlusive disease. This should clarify whether Omentin-1 is a suitable prognostic or therapeutic target for atherosclerotic disease.