Cyclic stretch of embryonic cardiomyocytes increases proliferation, growth, and expression while repressing Tgf-β signaling. (February 2015)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of molecular and cellular cardiology. Volume 79(2015:Feb.)
• Page Start: 133
• Page End: 144
• Publication Date: 2015-02
• Subjects: (HLHS) Hypoplastic Left Heart Syndrome -- (GO) Gene ontology -- (DMFM) Dynamic monolayer force microscopy -- (RNA-Seq) mRNA-sequencing -- (FDR) False discovery rate -- (EdU) 5-ethynyl-2′-deoxyuridine -- (qPCR) Quantitative Real Time PCR -- (SSC) Flow cytometry side scatter; Hypoplastic Left Heart Syndrome -- Mechanical stretch -- Cardiomyocytes -- Gene regulation -- Contractility -- Cardiac development; Subject Codes -- Pediatric and congenital heart disease -- Physiologic and pathologic control of gene expression -- Contractile function -- Other myocardial biology -- Cell biology/structural biology; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2014.11.003
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: 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.