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

J Mol Cell Cardiol. 2019 Jul:132:49-59. doi: 10.1016/j.yjmcc.2019.05.002. Epub 2019 May 7.

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 (GsαSMKO) were generated by cross-breeding Gsαflox/flox mice with SM22-CreERT2 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-/-/GsαSMKO than ApoE-/-/Gsαflox/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.

Keywords: Abdominal aortic aneurysm; Gsα; HuR; KLF4; Phenotype switch.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / toxicity*
  • Animals
  • Aortic Aneurysm, Abdominal / etiology*
  • Aortic Aneurysm, Abdominal / metabolism
  • Aortic Aneurysm, Abdominal / pathology
  • Disease Models, Animal
  • GTP-Binding Protein alpha Subunits, Gs / physiology*
  • Humans
  • Kruppel-Like Factor 4
  • Male
  • Mice
  • Mice, Knockout, ApoE
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phenotype
  • Signal Transduction
  • Vasoconstrictor Agents / toxicity*

Substances

  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • NF-kappa B
  • Vasoconstrictor Agents
  • Angiotensin II
  • GTP-Binding Protein alpha Subunits, Gs