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Molecular mechanism of mechanical stress-induced cardiac hypertrophy
1Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Japan.
Insights
Mechanical stress causes cardiac hypertrophy. Researchers identified ion channels and integrins as potential mechanoreceptors, crucial for understanding how mechanical load triggers heart cell growth and signaling pathways.
Area of Science:
- Cardiology
- Cell Biology
- Biochemistry
Background:
- Mechanical stress is a primary driver of cardiac hypertrophy.
- Understanding the biochemical mechanisms of load-induced cardiomyocyte hypertrophy has been limited by the lack of suitable in vitro models.
- Recent advancements in neonatal cardiocyte culture systems allow for detailed examination of mechanical stress signal transduction.
Purpose of the Study:
- To investigate the biochemical mechanisms underlying mechanical stress-induced cardiac hypertrophy.
- To identify the "mechanoreceptor" responsible for translating mechanical stimuli into intracellular biochemical signals in cardiomyocytes.
- To explore the role of vasoactive peptides in mediating hypertrophic responses to mechanical load.
Main Methods:
- Utilized an in vitro neonatal cardiocyte culture system with passive stretch applied to cells cultured on silicone membranes.
- Analyzed the activation of protein kinase phosphorylation cascades, including protein kinase C, Raf-1 kinase, and extracellular signal-regulated kinases.
- Measured gene expression, protein synthesis, and the production/secretion of vasoactive peptides like angiotensin II and endothelin.
Main Results:
- Passive stretch activated multiple protein kinase phosphorylation cascades.
- Mechanical stress induced specific gene expression and increased protein synthesis in cardiomyocytes.
- Production and secretion of vasoactive peptides, such as angiotensin II and endothelin, were elevated, playing key roles in hypertrophy.
- Evidence suggests that ion channels and integrins may function as the "mechanoreceptor" for mechanical stress.
Conclusions:
- Ion channels and integrins are potential candidates for the mechanoreceptor that initiates intracellular signaling in response to mechanical stress in cardiac myocytes.
- Vasoactive peptides significantly contribute to the hypertrophic development induced by mechanical load.
- The developed in vitro system provides a valuable tool for studying the molecular basis of mechanical stress-induced cardiac hypertrophy.
Abstract:
Mechanical stress is a major cause of cardiac hypertrophy. Although the mechanisms by which mechanical load induces cardiomyocyte hypertrophy have long been a subject of great interest for cardiologists, the lack of a good in vitro system has hampered the understanding of the biochemical mechanisms. For these past several years, however, an in vitro neonatal cardiocyte culture system has made it possible to examine the biochemical basis for the signal transduction of mechanical stress. Passive stretch of cardiac myocytes cultured on silicone membranes activates phosphorylation cascades of many protein kinases including protein kinase C, Raf-1 kinase and extracellular signal regulated kinases, and induces the expression of specific genes as well as an increase in protein synthesis. During that process, the secretion and production of vasoactive peptides such as angiotensin II and endothelin, are increased and they play critical roles in the induction of these hypertrophic responses. Although the involvement of vasoactive peptides in the development of cardiac hypertrophy is clinically important, the "mechanoreceptor" which receives the mechanical stress and converts it into intracellular biochemical signals remained unknown. We have recently obtained evidence suggesting that ion channels and integrins may be the "mechanoreceptor", the activation of which leads to cardiac hypertrophy.
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