51. CARDIAC STRETCH-INDUCED TRANSCRIPTOMIC CHANGES ARE DIRECTION DEPENDENT

Department: Bioengineering
Faculty Advisor(s): Jeffrey Omens | Andrew D. Mc Culloch

Primary Student
Name: Kyle Buchholz
Email: kbuchhol@ucsd.edu
Phone: 858-534-5796
Grad Year: 2016

Abstract
The goal of this study was to investigate the effect of the major axis of biaxial mechanical stretch on cardiomyocyte hypertrophic gene expression. Because cardiac hypertrophy can present itself as concentric or eccentric in vivo, we hypothesized that applying stretch in orthogonal directions to cardiomyocytes would produce divergent gene expression profiles. To investigate the directionally-dependent cellular response to stretch, neonatal mouse cardiomyocytes were cultured on a deformable silicone membrane, which was micropatterned to create parallel grooves that aligned the cardiomyocytes. By adjusting the groove orientation relative to the stretcher axes, the primary direction of stretch could be applied parallel or transverse to the myofibril direction. We conducted RNA sequencing (RNA-Seq) to examine whole genomic gene expression changes after acute cardiomyocyte stretch. The results showed a more robust gene response to longitudinal than to transverse stretch. After 30 minutes of stretch, 106 and 356 genes were considered differentially expressed (DE) from transverse and longitudinal stretch, respectively. After 4 hours, the number of DE genes increased to 184 and 1143. Gene ontology analysis indicated enrichment of transcription factor activity and protein kinase activity by both directions of stretch; whereas only longitudinal stretch caused enrichment of sarcomere organization and cytoskeletal protein binding. To further explore these gene expression changes, we constructed a logic-based gene regulatory network from published data. From this network analysis, we identified SRF as a critical transcription factor in regulating longitudinal stretch-induced gene changes and that SRF activity is modulated by calcium signaling. In addition, we found CREB to be a transcription factor activated by both longitudinal and transverse stretch. The regulatory network model provides evidence that cardiomyocytes engage different transcriptional regulators in response to different principal orientations of biaxial stretch.

Industry Application Area(s)
Life Sciences/Medical Devices & Instruments

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