Peptidyl-prolyl isomerase Pin1 deficiency attenuates angiotensin II-induced abdominal aortic aneurysm formation in ApoE-/- mice.
Peptidyl-prolyl isomerase Pin1 has been reported to be associated with endothelial dysfunction. However, the role of smooth muscle Pin1 in the vascular system remains unclear. Here, we examined the potential function of Pin1 in smooth muscle cells (SMCs) and its contribution to abdominal aortic aneurysm (AAA) pathogenesis. The level of Pin1 expression was found to be elevated in human AAA tissues and mainly localized to SMCs. We constructed smooth muscle-specific Pin1 knockout mice to explore the role of this protein in AAA formation and to elucidate the underlying mechanisms. AAA formation and elastin degradation were hindered by Pin1 depletion in the angiotensin II-induced mouse model. Pin1 depletion reversed the angiotensin II-induced pro-inflammatory and synthetic SMC phenotype switching via the nuclear factor (NF)-κB p65/Klf4 axis. Moreover, Pin1 depletion inhibited the angiotensin II-induced matrix metalloprotease activities. Mechanically, Pin1 deficiency destabilized NF-κB p65 by promoting its polyubiquitylation. Further, we found STAT1/3 bound to the Pin1 promoter, revealing that activation of STAT1/3 was responsible for the increased expression of Pin1 under angiotensin II stimulation. Thus, these results suggest that Pin1 regulates pro-inflammatory and synthetic SMC phenotype switching and could be a novel therapeutic target to limit AAA pathogenesis.
['Liang|Er-Shun|ES|', 'Cheng|Wen|W|', 'Yang|Rui-Xue|RX|', 'Bai|Wen-Wu|WW|', 'Liu|Xue|X|', 'Zhao|Yu-Xia|YX|']
D000804:Angiotensin II D000818:Animals D017544:Aortic Aneurysm, Abdominal D001057:Apolipoproteins E D002465:Cell Movement D049109:Cell Proliferation D016207:Cytokines D006801:Humans D018836:Inflammation Mediators D000090062:Kruppel-Like Factor 4 D051741:Kruppel-Like Transcription Factors D051379:Mice D018345:Mice, Knockout D008954:Models, Biological D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D016328:NF-kappa B D000072340:NIMA-Interacting Peptidylprolyl Isomerase D010641:Phenotype D011401:Promoter Regions, Genetic D050791:STAT Transcription Factors D015854:Up-Regulation
Pin1 Abdominal aortic aneurysm Smooth muscle Phenotype switching Klf4 Ubiquitylation