Abstract 284: Cyclic stretch of Embryonic Cardiomyocytes Increases Proliferation, Growth, and Expression While Repressing Tgf-β Signaling

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Abstract

Rationale: Perturbed biomechanical stimuli are critical for the pathogenesis of a number of congenital heart defects, including Hypoplastic Left Heart Syndrome (HLHS). While ventricular cardiomyocytes experience biomechanical stretch every heart beat, the molecular responses of embryonic cardiomyocytes to biomechanical stimuli are poorly understood. In this study, we examined how cyclic mechanical stretch modulates embryonic cardiomyocytes to improve understanding of normal and pathologic ventricular development. We hypothesize that biomechanical stimuli activates specific signaling pathways that impact proliferation, gene expression and myocyte contraction.

Objective: The objective for this study was to examine key molecular and phenotypic responses of embryonic cardiomyocytes to cyclic stretch that will provide a deeper understanding of HLHS.

Methods and Results: Embryonic mouse cardiomyocytes were exposed to cyclic stretch. Analysis of RNA-Sequencing data demonstrated that gene ontology (GO) groups associated with myofibril and cardiac development were significantly modulated. Stretch increased cardiomyocyte proliferation, size, and cardiac gene expression. Since the Tgf-β GO term was modulated by stretch, the role of Tgf-β in the cardiomyocyte response to stretch was examined. Stretched Cardiomyocytes had decreased Tgf-β expression, protein, and signaling. Functionally, Tgf-β signaling repressed cardiomyocyte proliferation, and both inotropic and chronotropic contractile function, which was assayed for confluent cell cultures by dynamic monolayer force microscopy (DMFM). Tgf-β inhibitor treatment resulted in increased cardiomyocyte size.

Conclusions: Herein, we observed that cyclic stretch promotes cardiomyocyte proliferation, growth, and gene expression. Stretch-mediated repression of Tgf-β appears to play a key role. Together these findings advance the understanding of how the biomechanical/molecular axis modulates ventricular development.

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