Abstract
Oxidized low-density lipoprotein (ox-LDL) accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9) is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function remain largely elusive. In the present study, the effects of CTRP9 on the proliferation, apoptosis, migration, angiogenesis, nitric oxide (NO) production and oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL were investigated. We observed that treatment with ox-LDL inhibited the proliferation, migration, angiogenesis and the generation of NO, while stimulated the apoptosis and reactive oxygen species (ROS) production in HUVECs. Incubation of HUVECs with CTRP9 rescued ox-LDL-induced endothelial injury. CTRP9 treatment reversed ox-LDL-evoked decreases in antioxidant enzymes including heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1, and glutamate-cysteine ligase (GCL), as well as endothelial nitric oxide synthase (eNOS). Furthermore, CTRP9 induced activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC1-α) and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Of interest, AMPK inhibition or PGC1-α silencing abolished CTRP9-mediated antioxidant enzymes levels, eNOS expressions, and endothelial protective effects. Collectively, we provided the first evidence that CTRP9 attenuated ox-LDL-induced endothelial injury by antioxidant enzyme inductions dependent on PGC-1α/AMPK activation.
Highlights
Vascular lesion is one of the most important complications in many cardiovascular diseases including atherosclerosis [1]
The apoptosis of human umbilical vein endothelial cells (HUVECs) upon to Oxidized low-density lipoprotein (ox-LDL) was obviously prevented by C1q/TNF-related protein 9 (CTRP9) (Figure 1F,I)
HUVECs exhibited increased reactive oxygen species (ROS) accumulation, and decreased the levels of antioxidant enzymes including heme oxygenase-1 (HO-1), NQO-1, GCLC, and GCLM after ox-LDL stimulation (Figure 2). dihydroethidium (DHE) (Figure 2A,C) or 2,7 -dichlorofluorescein diacetate (DCFH-DA) (Figure 2B,D) fluorescent dye showed that the productions of superoxide anions were increased in ox-LDL-stimulated HUVECs, which were abrogated by CTRP9
Summary
Vascular lesion is one of the most important complications in many cardiovascular diseases including atherosclerosis [1]. Endothelial cells are key components in the vascular endothelium, which can produce numerous factors that modulate angiogenesis, inflammation, oxidative stress, nitric oxide (NO) production, vascular tone, and permeability [6]. The endothelial cell apoptosis is involved in the pathogenesis of atherosclerosis [8]. C1q-TNF-related protein-9 (CTRP9), the closest adiponectin paralog, functions as a critical regulator in vascular relaxation [12], myocardial injury [13], and vascular smooth muscle cell proliferation [14]. CTRP9 abrogates tumor necrosis factor α-induced endothelial inflammation [17]. These extensive observations suggest that CTRP9 may critically participate in the vascular homeostasis. Whether and how CTRP9 was involved in endothelial dysfunction in response to ox-LDL remained largely obscure. We investigated the potential roles of CTRP9 in ox-LDL-stimulated endothelial injury and the underlying molecular mechanisms
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