The term 'mechanosensation' describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This capacity is related not only to the sensitivity of the cells to tissue motion, but also to the decryption of tissue geometric arrangement and mechanical properties. The cardiac stroma, composed of fibroblasts, has been historically considered a mechanically passive component of the heart. However, the latest research suggests that the mechanical functions of these cells are an active and necessary component of the developmental biology programme of the heart that is involved in myocardial growth and homeostasis, and a crucial determinant of cardiac repair and disease. In this Review, we discuss the general concept of cell mechanosensation and force generation as potent regulators in heart development and pathology, and describe the integration of mechanical and biohumoral pathways predisposing the heart to fibrosis and failure. Next, we address the use of 3D culture systems to integrate tissue mechanics to mimic cardiac remodelling. Finally, we highlight the potential of mechanotherapeutic strategies, including pharmacological treatment and device-mediated left ventricular unloading, to reverse remodelling in the failing heart.

• MeSH
• fibroblasty patologie   MeSH
• lidé MeSH
• myokard patologie   MeSH
• remodelace komor MeSH
• srdeční komory patologie   MeSH
• srdeční selhání * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Myocardial recovery from ischemia-reperfusion (IR) is shaped by the interaction of many signaling pathways and tissue repair processes, including the innate immune response. We and others previously showed that sustained expression of the transcriptional co-activator yes-associated protein (YAP) improves survival and myocardial outcome after myocardial infarction. Here, we asked whether transient YAP expression would improve myocardial outcome after IR injury. After IR, we transiently activated YAP in the myocardium with modified mRNA encoding a constitutively active form of YAP (aYAP modRNA). Histological studies 2 d after IR showed that aYAP modRNA reduced cardiomyocyte (CM) necrosis and neutrophil infiltration. 4 wk after IR, aYAP modRNA-treated mice had better heart function as well as reduced scar size and hypertrophic remodeling. In cultured neonatal and adult CMs, YAP attenuated H2O2- or LPS-induced CM necrosis. TLR signaling pathway components important for innate immune responses were suppressed by YAP/TEAD1. In summary, our findings demonstrate that aYAP modRNA treatment reduces CM necrosis, cardiac inflammation, and hypertrophic remodeling after IR stress.

• MeSH
• adaptorové proteiny signální transdukční aplikace a dávkování   genetika   MeSH
• apoptóza účinky léků   MeSH
• editace RNA MeSH
• infiltrace neutrofily účinky léků   MeSH
• injekce intramuskulární MeSH
• kardiomegalie farmakoterapie   etiologie   MeSH
• kardiomyocyty metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• messenger RNA aplikace a dávkování   genetika   MeSH
• modely nemocí na zvířatech MeSH
• myokard imunologie   MeSH
• myokarditida farmakoterapie   etiologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• novorozená zvířata MeSH
• reperfuzní poškození myokardu komplikace   MeSH
• signální proteiny YAP MeSH
• transkripční faktory aplikace a dávkování   genetika   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• messenger RNA MeSH
• signální proteiny YAP MeSH
• transkripční faktory MeSH
• YAP1 protein, human MeSH Prohlížeč