Molecular mechanism of cardiac hypertrophy and development

Congestive heart failure is a major issues for cardiologists and to fully u nderstand heart failure, it is important to understand the mechanism of the development of cardiac hypertrophy. Hemodynamic overload, namely mechanica l stress, is a major cause of cardiac hypertrophy and to dissect the signal ing pathways from mechanical stress to cardiac hypertrophy an in-vitro devi ce by which mechanical stress can be imposed on cardiac myocytes of neonata l rats cultured in serum-free conditions has been developed. Passively stre tching cardiac myocytes cultured on silicone membranes induced various hype rtrophic responses, such as activation of the phosphorylation cascades of m any protein kinases. expression of specific genes and an increase in protei n synthesis. During this process, secretion and production of vasoactive pe ptides, such as angiotensin II and endothelin-l, were increased and they pl ayed critical roles in the induction of these hypertrophic responses. Candi dates for the 'mechanoreceptor' that receives the mechanical stress and con verts it into intracellular biochemical signals have been recently demonstr ated. Gene therapy and cell transplantation are hopeful strategies for the treatment of heart failure and require an understanding of how normal cardi ac myocytes are differentiated. A key gene that plays a critical role in ca rdiac development has been isolated. The cardiac homeobox containing gene C ss is expressed in the heart and the heart progenitor cells from the very e arly developmental stage and targeted disruption of the murine Csx results in embryonic lethality because of 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 upregulat ion of cardiac genes. Mutations of human CSX cause various congenital heart diseases including atrial septal defect, ventricular septal defect, tricus pid valve abnormalities and atrioventricular block.