Abstract 678: Thoracic Aortic Dissection in Hypertensive Myh11r247c Mice Is Regulated by Gsk3β Signaling Pathway.

Abstract

Acute ascending aortic dissections cause premature deaths due to pericardial tamponade. Mutations in the gene for smooth muscle specific myosin heavy chain (MYH11) causes aortic dissections with minimal aortic dilation, whereas mutations in fibrillin-1 (FBN1) causing Marfan syndrome is characterized by aneurysm formation before dissections occur. We hypothesize that distinct pathways might be responsible for the aortic dissections. Results: Mice with a homozygous Myh11 missense variant (R247C), Myh11R247C, do not have aortic enlargement and do not die prematurely of aortic dissections. Increased blood pressure induced by high salt diet and L-NAME in the Myh11R247C mice leads to sudden death that occur within 2 weeks due to acute aortic dissection and pericardial tamponade in more than 20% (9/39) of the animals (P=0.02, comparing to the death rate (1/45) in WT mice). Increased SMC proliferation and accumulation of proteoglycans are observed in the aortas of the hypertensive Myh11R247C mice. RNA Seq analysis of the Myh11R247C aortas with and without hypertension indicated targets of the Wnt pathway were increased and pathway analysis with DAVID Bioinformatics Resources identified the focal adhesion pathway was highly involved (P<0.01). Immunoblot analysis of aortic lysates confirmed increased activation of FAK and AKT, along with phosphorylation (inactivation) of GSK3β when hypertension was induced. To further inhibit GSK3β in the hypertensive Myh11R247C, the GSK3β inhibitor SB216763 was given immediately before and with hypertension induction. The death rates in Myh11R247C mutant mice but not in WT mice increased to 50% from 20% (P=0.02, N=22). Conclusion: FAK/AKT/GSK3β signaling pathway probably plays a pivotal role in acute aortic dissections in hypertensive Myh11R247C mutant mice. The SMC proliferation and proteoglycan accumulation could be important cellular pathological changes responsible for aortic dissections.