Biochemical and Biophysical Research Communications
Omentin-1 ameliorates the attachment of the leukocyte THP-1 cells to HUVECs by targeting the transcriptional factor KLF2
Introduction
Endothelial dysfunction is an important pathological status of endothelium in the wall of vessels. Endothelial dysfunction has been involved in the pathogenesis of various vascular diseases, including atherosclerosis [1]. In the past few decades, oxidation of low density lipoproteins (ox-LDL) has been widely investigated and reported as an essential regulator which contributes to vascular diseases and endothelial dysfunction [2]. Ox-LDL has been revealed to promote endothelial inflammation and to contribute to atherosclerosis in many stages including plaque formation, progression and destabilization [3,4]. Excessive oxidative stress and inflammatory insults caused by ox-LDL in arterial wall have been considered as crucial mechanisms of atherosclerosis [5]. One of the initial and critical events in the endothelium's response to ox-LDL stimuli is the expression of adhesion molecules such as vascular cell adhesion molecule (VCAM)-1 and E-selectin. These molecules cause the early attachment and rolling of leukocyte on the endothelial surface [6], and finally lead to the formation of atherosclerosis. Induction of VCAM-1 and E-selectin by ox-LDL is regulated by transcriptional factors in endothelium. The kruppel-like factor 2 (KLF2) is an important member of the kruppel-like factor family member [7]. KLF2 is extensively distributed in the nucleus of endothelium and acts as a “molecular switch” to regulate critical aspects of endothelial cell function in inflammatory disease states [8,9]. Interestingly, studies demonstrate that KLF2 is able to inhibit the pro-inflammatory cytokines-induced expression of adhesion molecules such as E-selectin and VCAM-1 [6].
Omentin-1, an important adipokine primarily secreted by stromal vascular cells in visceral adipose tissue, has been reported to distribute in diverse tissues, including heart, placenta, and pancreas [10]. Omentin-1 has been involved in different types of physiological processes including redox homeostasis, cardiovascular action, and anti-inflammatory response [11]. Omentin-1 is beneficial for enhancing insulin-stimulated glucose uptake by activating Akt signaling, which regulates downstream events such as glucose metabolism [12]. Moreover, decreased serum omentin-1 levels have been found to be associated with the presence and disease activity of inflammatory bowel disease (IBD) [13]. Importantly, counteractive effects of omentin-1 on atherosclerosis and ischemia-induced revascularization have been reported before [14]. High levels of plasma omentin have been found to be linked to the improvement of heart damage and function after reperfusion therapy in patients with acute myocardial infarction. Administration of human recombinant omentin ameliorated acute ischemic injury in the heart by suppressing myocyte apoptosis through both Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK)- and Akt-dependent mechanisms in a rodent disease model [15]. Intravenous administration of adenoviral vectors encoding human omentin (Ad-omentin) in mice attenuated neointimal formation after arterial injury and suppressed vascular smooth muscle cells (VSMCs) growth [16]. Systemic delivery of Ad-omentin enhanced blood flow recovery and capillary density in ischemic limbs of wild-type mice through stimulating an Akt and endothelial nitric oxide synthase (eNOS) signaling pathway [17]. In the current study, we aimed to investigate the effects of omentin-1 on ox-LDL- induced endothelial inflammation and to clarify the underlying mechanisms.
Section snippets
Cell culture, treatment, and transfection
Human umbilical vein endothelial cells (HUVECs) were purchased from ATCC, USA. Cells were maintained in endothelial cell growth medium (Lonza, USA) containing 2% fetal calf serum (FCS) and endothelial cell growth factors. Human recombinant omentin-1 produced in HEK 293 cells was obtained from Enzo Life Sciences, USA. HUVECs were treated with ox-LDL (100 mg/l) in the presence or absence of omentin-1 (150, 300 ng/ml) for 12 h or 24 h. For “Loss-of-function” experiments, HUVECs were transfected
Result
It is well known that attachment of monocytes to the surface of endothelial cells plays a pivotal role in the pathogenesis of atherosclerosis. Therefore, we set out to find out whether omentin-1 had an influence on adhesion of monocytes to HUVECs. As shown in Fig. 1, the numbers of THP-1 cells adhered to HUVECs were significantly increased by treatments with ox-LDL. However, omentin-1 significantly decreased the adhesion of THP-1 cells to the surface of HUVECs in a dose dependent manner.
Discussion
It is well known that the atherosclerotic lesion is characterized by an accumulation of lipids carried by lipoproteins, such as low-density lipoprotein (LDL). LDL becomes susceptible to (non) enzymatic oxidative modifications when retained in the artery wall. Ox-LDL plays a critical role in endothelial dysfunction and contributes to the atherosclerotic plaque formation, progression and destabilization [19,20]. Blockage of ox-LDL- induced endothelial inflammation has been considered as an
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