Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice

Abstract

Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein-E knockout (apoE-KO) mice. Methods and Results ApoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate ApoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. ApoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apo-E KO mice. ApoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibers in response to Ang II compared with apo-E KO mice. ApoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2 and pro-inflammatory genes in aortic walls compared with apo-E KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibers in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide (LPS). Treatment of human vascular smooth muscle cells with omentin protein reduced expression and activation of MMP2 after stimulation with tumor necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and vascular smooth muscle cells. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signaling in macrophages and vascular smooth muscle cells, respectively. Conclusion These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.

Omentin Modulates Chronic Cardiac Remodeling After Myocardial Infarction

“…17 in a background of apolipoprotein E deficiency. 18, 19 Moreover, we have shown that omentin reduces myocardial injury after ischemia-reperfusion and attenuated cardiac hypertrophy directly after pressure overload. 20, 21 Other groups have reported that omentin protects against glucocorticoid-induced cardiac injury and docetaxel cardiotoxicity.…”

“… 16 We also demonstrated that omentin reduced neointimal thickness in injured arteries, 17 and that omentin prevents the formation of atherosclerotic lesions and abdominal aortic aneurysms after angiotensin II infusion in a background of apolipoprotein E deficiency. 18 , 19 Moreover, we have shown that omentin reduces myocardial injury after ischemia-reperfusion and attenuated cardiac hypertrophy directly after pressure overload. 20 , 21 Other groups have reported that omentin protects against glucocorticoid-induced cardiac injury and docetaxel cardiotoxicity.…”

Regulation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Abdominal Aortic Aneurysm

“…The suppressive effects of omentin on MMP-9 and MMP-2 expression could be reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signaling. [85] Another study showed that inflammatory monocyte/macrophage invasion and MMP-9 activity were enhanced by VSMC-specific over-expression of prostaglandin E receptor 4 (EP4) during the initial stage of AAA formation in mice, and EP4 stimulation induced marked IL-6 production via TGF-β-activated kinase 1, NF-κB, JNK, and p38 MAPK. [86] Inhibitor of kappa B kinase epsilon deficiency attenuates MMP-2 and MMP-9 expression and activation in Ang II-induced AAA through blunting activation of the ERK1/2 pathway.…”

“…[98] Factors that regulate MMP-2 and/or MMP-9 in AAA are summarized in Table 1. [45,52,58,59,[62][63][64][65][66][68][69][70][71][73][74][75][76][77][80][81][82][83][84][85][86][87][88][91][92][93][94][95][96][97][98] The related signals involved in regulating MMP-2 and MMP-9 in AAA pathologies are summarized in Figure 2.…”

“…Hydrogen peroxide-inducible clone 5 [84] Enhances MMP-2 activity In vivo/in vitro Omentin [85] Inhibits MMP-2 and MMP-9 activity In vivo/in vitro Prostaglandin E receptor 4 [86] Enhances MMP-9 activity In vivo Inhibitor of kappa B kinase epsilon [87] Enhances MMP-2 and MMP-9 activation In vivo/in vitro Interleukin-18 [88] Enhances MMP-2 and MMP-9 activation In vivo TIMP-1 [91] Inhibits MMP-2 and MMP-9 activity In vivo TIMP-2 [92] Cofactor for MMP-2 activation In vivo TIMP-3 [93] Inhibits MMP-2 activity In vivo TIMP-4 [94] Inhibits MMP-2 and MMP-9 activity In vivo Aliskiren [95] Inhibits MMP-2 and MMP-9 activation In vivo Rolipram [96] Inhibits MMP-2 activity In vivo Folic acid [97] Enhances MMP-2 AND MMP-9 activation In vivo Ang II peptide vaccine [98] Inhibits MMP-2 and MMP-9 activation In vivo AAA: Abdominal aortic aneurysm; Ang II: Angiotensin II; miR: MicroRNA; MMP: Matrix metalloproteinase; TIMP: Tissue inhibitor of metalloproteinase.…”