Abstract
Background and Purpose. Abdominal aortic aneurysm (AAA) is a chronic inflammatory disorder and the important causes of death among men over the age of 65 years. Interleukin-12p35 (IL12p35) is an inflammatory cytokine that participates in a variety of inflammatory diseases. However, the role of IL12p35 in the formation and development of AAA is still unknown. Experimental Approach. Male apolipoprotein E-deficient (Apoe−/−) mice were generated and infused with 1.44 mg/kg angiotensin II (Ang II) per day. We found that IL12p35 expression was noticeably increased in the murine AAA aorta and isolated aortic smooth muscle cells (SMCs) after Ang II stimulation. IL12p35 silencing promoted Ang II-induced AAA formation and rupture in Apoe−/− mice. IL12p35 silencing markedly increased the expression of inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), in both the serum and AAA aorta. Additionally, IL12p35 silencing exacerbated SMC apoptosis in Apoe−/− mice after Ang II infusion. IL12p35 silencing significantly increased signal transducer and activator of transcription (STAT) 4 phosphorylation levels in AAA mice, and STAT4 knockdown abolished the IL12p35-mediated proinflammatory response and SMC apoptosis. Interpretation. Silencing IL12p35 promotes AAA formation by activating the STAT4 pathway, and IL12p35 may serve as a novel and promising therapeutic target for AAA treatment.
Highlights
Abdominal aortic aneurysm (AAA) is a chronic inflammatory disorder and one of the important causes of death among men over the age of 65 years [1, 2]
IL12p35 protein levels were progressively elevated in the aorta from 1 to 4 weeks after angiotensin II (Ang II) infusion in the experimental AAA model mice compared with control mice (1.4, 1.9, and 2.6-fold at 1, 2, and 4 weeks, respectively) (Figure 1(a))
The results showed that Ang II stimulation significantly increased the mRNA expression of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), while IL12p35 silencing further increased the expression of those inflammatory markers (Figures 6(b)–6(d))
Summary
Abdominal aortic aneurysm (AAA) is a chronic inflammatory disorder and one of the important causes of death among men over the age of 65 years [1, 2]. The inflammatory response, oxidative stress, SMC apoptosis, and proteolytic degradation of aortic wall connective tissue have all Mediators of Inflammation been associated with the development of AAA [11, 12]. We found that IL12p35 expression was noticeably increased in the murine AAA aorta and isolated aortic smooth muscle cells (SMCs) after Ang II stimulation. IL12p35 silencing promoted Ang II-induced AAA formation and rupture in Apoe/- mice. IL12p35 silencing markedly increased the expression of inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), in both the serum and AAA aorta. IL12p35 silencing exacerbated SMC apoptosis in Apoe-/- mice after Ang II infusion. IL12p35 silencing significantly increased signal transducer and activator of transcription (STAT) 4 phosphorylation levels in AAA mice, and STAT4 knockdown abolished the IL12p35-mediated proinflammatory response and SMC apoptosis. Silencing IL12p35 promotes AAA formation by activating the STAT4 pathway, and IL12p35 may serve as a novel and promising therapeutic target for AAA treatment
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