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

• Published in: Journal of molecular and cellular cardiology Vol. 79; pp. 133 - 144
• Main Authors: Banerjee, Indroneal, Carrion, Katrina, Serrano, Ricardo, Dyo, Jeffrey, Sasik, Roman, Lund, Sean, Willems, Erik, Aceves, Seema, Meili, Rudolph, Mercola, Mark, Chen, Ju, Zambon, Alexander, Hardiman, Gary, Doherty, Taylor A., Lange, Stephan, del Álamo, Juan C., Nigam, Vishal
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2015
• Subjects: Animals; Cardiac development; Cardiomyocytes; Cardiovascular; Cell Proliferation - drug effects; Cell Size; Contractility; Embryo, Mammalian - cytology; Gene Expression Regulation - drug effects; Gene Ontology; Gene regulation; Hypoplastic Left Heart Syndrome; Mechanical stretch; Mice; Myocardial Contraction - drug effects; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myofibrils - metabolism; Sequence Analysis, RNA; Signal Transduction - drug effects; Stress, Mechanical; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; SSC; Other myocardial biology; Gene regulation; Contractile function; Contractility; GO; Cardiomyocytes; Cardiac development; Pediatric and congenital heart disease; HLHS; DMFM; Cell biology/structural biology; RNA-Seq; FDR; Subject Codes; Mechanical stretch; EdU; Hypoplastic Left Heart Syndrome; qPCR; Physiologic and pathologic control of gene expression; Gene ontology; mRNA-sequencing; 5-ethynyl-2′-deoxyuridine; Dynamic monolayer force microscopy; Quantitative Real Time PCR; False discovery rate; Flow cytometry side scatter
• ISSN: 0022-2828; 1095-8584; 1095-8584
• DOI: 10.1016/j.yjmcc.2014.11.003

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. •Biomechanical stimuli are altered in Hypoplastic Left Heart Syndrome.•Mechanical stimuli activate signaling pathways and regulate embryonic cardiomyocyte function.•Tgf-β signaling altered embryonic cardiomyocytes function (proliferation and size).•Dynamic Force Microscopy found decreased contractile function under Tgf-β stimulation.•Data supports the hypothesis that mechanical stimuli are key for cardiac development.