mechanical stress

angiotensin II

development

homeobox

To understand the heart failure, it is important to elucidate the mechanism of the development of cardiac hypertrophy. Hemodynamic overload, namely mechanical stress, is a major cause for cardiac hypertrophy. To dissect the signaling pathways from mechanical stress to cardiac hypertrophy, we developed the in vitro device by which mechanical stress can be imposed on cardiac myocytes of neonatal rats cultured in the serum-free condition. Passive stretch of cardiac myocytes cultured on silicone membranes induced various hypertrophic responses such as activation of phosphorylation cascades of many protein kinases, expression of specific genes and an increase in protein synthesis. During this process, secretion and production of vasoactive peptides such as angiotensin II and endothelin-1, are increased and they played critical roles in the induction of these hypertrophic responses. Recently candidates for the "mechanoreceptor" which receive mechanical stress and convert it into intracellular biochemical signals have been demonstrated. To treat heart failure, gene therapy and cell transplantation are hopeful strategies. To enable these novel treatments, it is important to understand how normal cardiac myocytes are differentiated. We have isolated a key gene which plays a critical role in cardiac development. A cardiac homeobox-containing gene Csx is expressed in the heart and the heart progenitor cells from the very early developmental stage, and targeted disruption of the murine Csx results in embryonic lethality due to the abnormal looping morphogenesis of the primary heart tube. With a cardiac zinc finger protein GATA4, Csx induces cardiomyocyte differentiation of teratocarcinoma cells as well as upregulation of cardiac genes. Mutations of human Csx cause various congenital heart diseases including atrial septal defect, ventricular septal defect, tricuspid valve abnormalities and atrioventricular block.