Role of smooth muscle YAP and TAZ in protection against phenotypic modulation, inflammation, and aneurysm development

Biochem Pharmacol. 2022 Dec:206:115307. doi: 10.1016/j.bcp.2022.115307. Epub 2022 Oct 19.

Abstract

A ruptured arterial aneurysm, especially in the aorta, represents one of the most acute and mortal conditions encountered in clinical medicine. Population-based screening in elderly men, treatment of risk factors, such as hypertension, and endovascular or open repair of rupture-prone lesions, represent cornerstones in management. Surgical repair has a sizeable effect on life-expectancy, but medical therapy that retards aneurysm growth still represents a considerable and unmet clinical need. In the current review we survey recent findings implicating the mechano-responsive transcriptional co-activators YAP and TAZ in protection from aneurysm development. Arteries from mouse mutants that lack YAP and TAZ in vascular smooth muscle respond inadequately to mechanical stimulation, and they develop aneurysms characterized by elastin fragmentation, proteoglycan infiltration, and severe inflammation at breathtaking speed. This seems to be due, at least in part, to unscheduled activation of STING (stimulator of interferon genes), an arm of innate immunity that responds to double-stranded DNA in the cytoplasm. YAP and TAZ protect from STING activation by securing nuclear integrity. These novel insights suggest unanticipated medical therapies for sporadic and genetic aneurysms alike, involving inhibition of kinases in the Hippo pathway using small molecules, or inhibition of STING signaling itself. Translation of these novel findings into clinical therapies now represents an important priority.

Keywords: Cardiovascular disease; Contraction; Dilatation; MYOCD; Myocardial infarction; WWTR1; YAP1; cGAMP; cGAS.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Aneurysm*
  • Animals
  • Cell Proliferation
  • Inflammation
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Muscle, Smooth, Vascular / metabolism
  • Phosphoproteins / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • Intracellular Signaling Peptides and Proteins
  • Trans-Activators
  • YAP-Signaling Proteins
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Transcription Factors