Deletion of resistin-like molecule-beta attenuates angiotensin II-induced abdominal aortic aneurysm.

Abstract

In the present study, we want to test whether deletion of resistin-like molecule-beta (RELMβ) attenuates angiotensin II (Ang II)-induced formation of abdominal aortic aneurysm (AAA). RELMβ gene expression was inhibited by siRNA both in vivo and in vitro. Apolipoprotein E-knockout (ApoE−/−) mice were randomly divided into saline, Ang II, siRNA negative control (si-NC) and siRNA RELMβ (si-RELMβ) groups (n=15 each), and mice in the last three groups underwent Ang II infusion for 4 weeks to induce AAA. RELMβ gene deficiency significantly decreased AAA incidence and severity, which was associated with reduced macrophage accumulation and decreased expression of proinflammatory cytokines (monocyte chemoattractant protein 1 and interleukin 6), matrix metalloproteinase 2 (MMP-2) and MMP-9 in the aortic wall. In cultured macrophages, RELMβ deficiency blunted the response of macrophages to Ang II and downregulated the levels of proinflammatory cytokines, MMP-2 and MMP-9. Recombinant RELMβ promoted the secretion of proinflammatory cytokines, MMP-2 and MMP-9 in macrophages and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) signaling, which was reversed with pretreatment with inhibitors of ERK1/2 and JNK. Deletion of RELMβ attenuated Ang II-induced AAA formation in ApoE−/− mice. The inherent mechanism may involve the reduced expression of proinflammatory cytokines, MMP-2 and MMP-9, which was mediated by ERK1/2 and JNK activation. Therefore, inhibiting RELMβ secretion may be a novel approach for anti-aneurysm treatment.