CAP2 loss activated MRTF/SRF signaling through actin dynamics in cardiomyocytes

[Speaker] Yao Xiong:1
[Co-author] Georgina K Cox:1, Kenneth Bedi:2, Kenneth B Margulies:2, Simon Berritt:3, Jeffrey M Field:1
1:Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, USA, 2:Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, USA, 3:Department of Chemistry, Merck High throughput Experimentation Laboratory, University of Pennsylvania, USA

Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that causes developmental disorders and confers a risk for sudden cardiac death and conduction disease is located at 6p22, near the cytoskeletal gene, CAP2. CAP2 regulates actin dynamics in the cytoskeleton by binding actin monomers and assisting filament severing to modulate the balance of filamentous actin (F-actin) and globular actin (G-actin). To determine the role of CAP2 in vivo, we generated a whole-body knockout (KO) mice model. Previously data shows CAP2 KO males were underrepresented (Mendelian ratios 5%, expected 25%) and ~70% died of sudden cardiac death by 12 weeks of age, but females were found at close to the expected levels (17%) and lived normal lifespans. While the strong sex bias lost in our cardiomyoctes specific knockout mice and all mice died suddenly due to complete heart block. RNA-seq analysis of CAP2 KO hearts revealed an over-activation of actin dynamics regulated MRTF/SRF transcription signaling, which is known to be critical for heart development and function. The over-activated SRF signaling is specific in cardiomyocytes through ages by detecting its downstream genes expression, Myl-9 and Acta-2, determined by qPCR. Additionally, we synthesized a new compound CCG-1423-8a which can inhibit SRF transcription activity by inhibiting MRTF translocate into the nuclei both in vivo and in vitro. Our study establishes a direct model of how actin dynamics plays a role in sudden cardiac death and cardiac conduction disease.

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