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
• Fibroblasts pathology   MeSH
• Humans MeSH
• Myocardium pathology   MeSH
• Ventricular Remodeling MeSH
• Heart Ventricles pathology   MeSH
• Heart Failure * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review 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
• Adaptor Proteins, Signal Transducing administration & dosage   genetics   MeSH
• Apoptosis drug effects   MeSH
• RNA Editing MeSH
• Neutrophil Infiltration drug effects   MeSH
• Injections, Intramuscular MeSH
• Cardiomegaly drug therapy   etiology   MeSH
• Myocytes, Cardiac metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• RNA, Messenger administration & dosage   genetics   MeSH
• Disease Models, Animal MeSH
• Myocardium immunology   MeSH
• Myocarditis drug therapy   etiology   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Animals, Newborn MeSH
• Myocardial Reperfusion Injury complications   MeSH
• YAP-Signaling Proteins MeSH
• Transcription Factors administration & dosage   genetics   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• RNA, Messenger MeSH
• YAP-Signaling Proteins MeSH
• Transcription Factors MeSH
• YAP1 protein, human MeSH Browser