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J Mol Cell Cardiol. 2015 Feb;79:133-44. doi: 10.1016/j.yjmcc.2014.11.003. Epub 2014 Nov 13.

Cyclic stretch of embryonic cardiomyocytes increases proliferation, growth, and expression while repressing Tgf-β signaling.

Author information

1
Department of Cardiology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
2
Department of Pediatrics (Cardiology), University of California San Diego, United States.
3
Department of Mechanical and Aerospace Engineering, University of California San Diego, United States.
4
Biomedical Genomics Microarray Core Facility, University of California San Diego, United States.
5
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
6
Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, United States.
7
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States; Department of Pediatrics (Allergy), University of California San Diego, United States; Rady Children's Hospital San Diego, United States.
8
Department of Mechanical and Aerospace Engineering, University of California San Diego, United States; Cell and Developmental Biology, University of California San Diego, United States.
9
School of Pharmacology Keck Graduate Institute, 9500 Gilman Drive, La Jolla, CA 92093, United States.
10
Department of Medicine, Medical University of South Carolina, 135 Cannon Street, Suite 303 MSC 835, Charleston, SC 29425, United States.
11
Department of Mechanical and Aerospace Engineering, University of California San Diego, United States; Institute for Engineering in Medicine, University of California San Diego, United States.
12
Department of Pediatrics (Cardiology), University of California San Diego, United States; Rady Children's Hospital San Diego, United States; Institute for Engineering in Medicine, University of California San Diego, United States. Electronic address: vnigam@ucsd.edu.

Abstract

Perturbed biomechanical stimuli are thought to be critical for the pathogenesis of a number of congenital heart defects, including Hypoplastic Left Heart Syndrome (HLHS). While embryonic cardiomyocytes experience biomechanical stretch every heart beat, their molecular responses to biomechanical stimuli during heart development are poorly understood. We hypothesized that biomechanical stimuli activate specific signaling pathways that impact proliferation, gene expression and myocyte contraction. The objective of this study was to expose embryonic mouse cardiomyocytes (EMCM) to cyclic stretch and examine key molecular and phenotypic responses. Analysis of RNA-Sequencing data demonstrated that gene ontology groups associated with myofibril and cardiac development were significantly modulated. Stretch increased EMCM proliferation, size, cardiac gene expression, and myofibril protein levels. Stretch also repressed several components belonging to the Transforming Growth Factor-β (Tgf-β) signaling pathway. EMCMs undergoing cyclic stretch had decreased Tgf-β expression, protein levels, and signaling. Furthermore, treatment of EMCMs with a Tgf-β inhibitor resulted in increased EMCM size. Functionally, Tgf-β signaling repressed EMCM proliferation and contractile function, as assayed via dynamic monolayer force microscopy (DMFM). Taken together, these data support the hypothesis that biomechanical stimuli play a vital role in normal cardiac development and for cardiac pathology, including HLHS.

KEYWORDS:

Cardiac development; Cardiomyocytes; Contractility; Gene regulation; Hypoplastic Left Heart Syndrome; Mechanical stretch

PMID:
25446186
PMCID:
PMC4302020
DOI:
10.1016/j.yjmcc.2014.11.003
[Indexed for MEDLINE]
Free PMC Article

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