Vascular Transcriptome Profiling Reveals Aging-Related Genes in Angiotensin Ji-Induced Hypertensive Mouse Aortas

Objective AngiotensinⅡ(AngⅡ)-induced vascular damage is a major risk of hypertension.However,the underlying molecular mechanism of AngⅡ-induced vascular damage is still unclear.In this study,we explored the novel mechanism associated with Ang Il-induced hypertension.Methods We treated 8-to 12-week-old C57BL/6J male mice with saline and AngⅡ(0.72 mg/kg-d)for 28 days,respectively.Then the RNA of the media from the collected mice aortas was extracted for transcriptome sequencing.Principal component analysis was applied to show a clear separation of different samples and the distribution of differentially expressed genes was manifested by Volcano plot.Functional annotations including Gene Ontology(GO)and Koto Encyclopedia of Genes and Genomes(KEGG)pathway were performed to reveal the molecular mechanism of AngⅡ-induced hypertension.Finally,the differentially expressed genes were validated by using quantitative real-time PCR.Results The result revealed that a total of 773 genes,including 599 up-regulated genes and 174 down-regulated genes,were differentially expressed in the aorta of AngⅡ-induced hypertension mice model.Functional analysis of differentially expressed genes manifested that various cellular processes may be involved in the AngⅡ-induced hypertension,including some pathways associated with hypertension such as extracellular matrix,inflammation and immune response.Interestingly,we also found that the differentially expressed genes were enriched in vascular aging pathway,and further validated that the expression levels of insulin-like growth factor 1 and adiponectin were significantly increased(P<0.05).Conclusion We identify that vascular aging is involved in AngⅡ-induced hypertension,and insulin-like growth factor 1 and adiponectin may be important candidate genes leading to vascular aging.

Mouse macrophage specific knockout of SIRT1 influences macrophage polarization and promotes angiotensin Ⅱ-induced abdominal aortic aneurysm formation

Abdominal aortic aneurysm （AAA） is a vascular degenerative disease. Macrophage polarization and the balance between classically activated macrophages （M1） and alternatively activated macrophages （M2） are crucial for AAA pathogenesis. The present study aims to investigate the roles of macrophage SIRTI in AAA formation and macrophage polarization. We found that in mouse peritoneal macrophages, SIRT1 expression was decreased after M1 stimulation, but was enhanced after M2 stimulation. Results from SIRT1flox/flox mice and macrophage specific SIRT1 knockout mice with treatment of angiotensin II （Ang 11） for 4 weeks showed that macropbage specific deficiency of SIRT1 increased the incidence of AAA and exacerbated the severity, including more severe aneurysm types, enlarged diameter of the aneurysm and increased degradation of elastin. In mouse aortas, SIRT1 deficiency increased the pro- inflammatory M1 molecule inducible nitric oxide synthase （iNOS）, and decreased M2 molecules such as arginase 1 （Argl） and mannose receptor （MR）. Furthermore, in peritoneal macrophages, SIRT1 deficiency increased the expression of M1 inflammatory molecules, but decreased the expression of M2 molecules. Overexpression of SIRT1 had the opposite effects. Thus, macrophage specific knockout of SIRT1 influences macrophage polarization and accelerates Ang II-induced AAA formation.