A Pathogenic ROCK-Signaling Network Involving a Lysine Deletion in Myh11 Renders Carriers Susceptible to Aortic...

Area of Science:

• Genomics and Molecular Biology
• Cardiovascular Research
• Systems Biology

Background:

• Familial thoracic aortic aneurysm and dissection (FTAAD) results from the Myh11 K1256del variant, leading to reduced aortic contractility.
• The precise mechanisms by which impaired contractility increases dissection risk are not fully understood.

Purpose of the Study:

• To identify key regulatory mechanisms in FTAAD using a trans-omic approach in Myh11 K1256del mice.
• To explore potential therapeutic targets and interventions for FTAAD.

Main Methods:

• Data-driven trans-omic upstream analysis using Genome Enhancer on mouse aortas.
• Transcriptome analysis to identify gene expression patterns.
• Computational analysis of regulatory regions and druggability.

Main Results:

• Transcriptome analysis showed enrichment of genes involved in smooth muscle contraction and myosin light chain phosphatase activity.
• Key transcription factors identified include nuclear factor of activated T cells 1 and lymphoid enhancer-binding factor 1.
• Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) was predicted as a central regulator, with ROCK1 and JunB as potential therapeutic targets. 51 candidate drugs were identified.

Conclusions:

• Aortic tissue with the Myh11 K1256del variant exhibits a ROCK signaling-centered transcriptional program even without external stimuli.
• This ROCK signaling may predispose the aorta to dissection by priming it for maladaptive responses to stress.
• Findings provide a hypothesis for developing preventive pharmacological interventions against FTAAD, requiring experimental validation.