Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo. (July 2019)

• Record Type: Journal Article
• Authors: Qin, Xiaoteng; He, Lifan; Tian, Mi; Hu, Ping; Yang, Jianmin; Lu, Huixia; Chen, Wenqiang; Jiang, Xiuxin; Zhang, Cheng; Gao, Jiangang; Chen, Min; Weinstein, Lee S.; Zhang, Yun; Zhang, Wencheng
• Is Part Of: Journal of molecular and cellular cardiology. Volume 132(2019)
• Page Start: 49
• Page End: 59
• Publication Date: 2019-07
• Subjects: Abdominal aortic aneurysm -- Gsα -- Phenotype switch -- HuR -- KLF4; AAA Abdominal aortic aneurysm -- AngII angiotensin II -- ARE adenylate uridylate-rich element -- α-SMA SM α-actin -- cAMP cyclic adenosine monophosphate -- Gsα alpha-subunit of the stimulatory G protein -- GsαSMKO smooth muscle-specific Gsα knockout -- HuR human antigen R -- KLF4 Krüppel-like factor 4 -- SMCs Smooth muscle cells -- UTR untranslated region; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.05.002
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Objective: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Genetic studies have proved the involvement of smooth muscle phenotype switch in the development of AAA. The alpha subunit of the heterotrimeric G stimulatory protein (Gsα) mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP). However, the role of smooth muscle Gsα in AAA formation remains unknown. Approach and results: In this study, mice with knockout of smooth muscle-specific Gsα (Gsα SMKO ) were generated by cross-breeding Gsα flox/flox mice with SM22-CreER T2 transgenic mice, induced in adult mice by tamoxifen treatment. Gsα deficiency induced a smooth muscle phenotype switch from a contractile to a synthetic state. Mechanically, Gsα deletion reduced cAMP level and increased the level of human antigen R (HuR), which binds with the adenylate uridylate–rich elements of the 3′ untranslated region of Krüppel-like factor 4 (KLF4) mRNA, thereby increasing the stability of KLF4. Moreover, genetic knockdown of HuR or KLF4 rescued the phenotype switch in Gsα-deficient smooth muscle cells. Furthermore, with acute infusion of angiotensin II, the incidence of AAA was markedly higher in ApoE −/− /Gsα SMKO than ApoE −/− /Gsα flox/flox mice and induced increased elastic lamina degradation and aortic expansion. Finally, the levels of Gsα and SM α-actin were significantly lower while those of HuR and KLF4 were higher in human AAA samples than adjacent nonaneurysmal aortic sections. Conclusions: Gsα may play a protective role in AAA formation by regulating the smooth muscle phenotype switch and could be a potential therapeutic target for AAA disease. Highlights: Smooth muscle phenotype switch involves in the development of AAA (abdominal aortic aneurysm). Gsα deficiency induced the smooth muscle phenotype switch via the HuR/KLF4 pathway. Smooth muscle-specific Gsα deletion exaggerated AngII-induced AAA formation. Gsα expression was significantly reduced in the mouse and human AAA samples.