Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

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 receptorstimulated 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.is often accompanied by downregulation of multiple contractile proteins in aortic smooth muscle cells (SMCs) [4,5]. Furthermore, aortic intimal layer injury and inflammatory cell infiltration participate in the aneurysm progression via complicated mechanisms such as cytokine secretion and increased reactive oxygen species levels [3,6]. Finally, vascular collagen and elastin extracellular matrix is thought to undergo degradation by matrix metalloproteinases and contribute to AAA

circ_TGFBR2 Inhibits Vascular Smooth Muscle Cells Phenotypic Switch and Suppresses Aortic Dissection Progression by Sponging miR-29a

“… 38 Gsa deletion decreased cAMP level and increased HuR expression, which binds to the adenylate uridylate-rich elements of the 3ʹ untranslated region of KLF4 mRNA, thus regulating angiotensin II–induced abdominal aortic aneurysm formation. 34 In our study, our results suggested that circ_TGFBR2/miR-29a/KLF4 axis mediated AD-VSMCs proliferation, migration and phenotypic switching. Although the upregulation of KLF4 by circ_TGFBR2 mediates AD promotion, more mechanistic details about KLF4 involved are still needed and will be our next research stage.…”

“… 33 Previous research had revealed that KLF4 gene was relevant with various vascular diseases, including abdominal aortic aneurysms and atherosclerosis. 34 , 35 Also, KLF4 has been identified as a key factor required for VSMCs cells phenotypic modulation. 36 For the function of KLF4 in VSMCs phenotype switch, there are two conflicting opinions: KLF4 inhibits VSMCs phenotype switch and KLF4 promotes VSMCs phenotype regulation.…”

MicroRNA‐199a‐5p aggravates angiotensin II–induced vascular smooth muscle cell senescence by targeting Sirtuin‐1 in abdominal aortic aneurysm

“…Abdominal aortic aneurysm (AAA), characterized by degradation of the aortic wall and a progressively enlarged aorta that exceeds the normal diameter by > 50%, is a leading cause of morbidity and mortality worldwide. 1 It is an age‐related vascular disease with an incidence as high as 8% in males aged > 60 years and females aged >65 years. 2 There is no effective pharmacological treatment to prevent, delay or reverse AAA 3 so a novel pharmacotherapy is urgently needed.…”

Silencing IL12p35 Promotes Angiotensin II-Mediated Abdominal Aortic Aneurysm through Activating the STAT4 Pathway

“…The maximal aortic diameter was measured using the ImageJ software (NIH, USA). Aneurysm formation was identified as an enlargement >50% of the diameter compared with that of mice without Ang II infusion as described previously [23]. In addition, the incidence of aneurysms and the survival rate were monitored and calculated.…”