Myocardial Hypertrophy Calcineurin Phosphatase, Mitogen-activated Protein Kinase Phosphorylation Regulation And Reversal Mechanism

BACKGROUNDCardiac hypertrophy is initially an adaptive response that temporarily augments or maintains cardiac output, decreased wall tension. Sustained cardiac hypertrophy not only results in congestive heart failure but also causes life threatening cardiac diseases such as myocardial infarction, malignant arrhythmia, and sudden death. Therefore, it is very important to understand the underlying mechanisms of cardiac hypertrophy and prevent or treat it in the purpose.Calcineurin (CaN) and mitogen-activated protein kinase (MAPK) can induce cardiac hypertrophy through dephosphorylate or phosphorylate the downstream targets. CaN is the only serine/threonine protein phosphatase under the control of Ca2+/calmodulin which molecular weight is 80KD. It is found that CaN is mainly located in the cytoplasm and is broadly distributed. In 80s, CaN was originally identified in the extract of mammalian brain which was one of the most abundant protease. Within the past few years this phosphatase has been implicated in a wide variety of biological responses including lymphocyte activation, neuronal and muscle development, and morphogenesis of vertebrate heart valves. In 1998, Molkentin et al first demonstrated the importance of CaN and its downstream transcription factor NFAT3 in the development of cardiac hypertrophy. Recently it has been demonstrated that CaN participates in the hypertrophy caused by a number of physiological related stimuli and the mutations of sarcomeric protein genes. It is assumed that CaN may play a critical role in the coupling of Ca2+ signaling to the fetal cardiac genes expression. Whereas the association between CaN and cardiac hypertrophy was centered on the period of development, it is not known if CaN activity is required for the long-term maintenance of cardiac pathologic responses, and whether suppression of CaN induces the regression of cardiac hypertrophy once cardiac hypertrophy develops inthe renovascular hypertension. Mitogen-activated protein kinases could be rapidly activated by many of extracellular stimuli, and it is conceived that MAPK is the convergent point or common signaling pathway of intracellular signaling conduction during hyperplasia or hypertrophy of cells. The superfamily includes 3 major pathways: the extracellular-signal regulated kinases, c-Jun NIC-terminal kinase and p38 protein kinase. However, the researches about MAPK were centralized on the level of activity, some on the level of protein, while there is no research on the level of gene about MAPK. CaN and MAPK, as important signaling pathways mediated cardiac hypertrophy, their relationship needs further research. OBJECTIVE:To investigate the changes of the level of CaN mRNA expression, protein expression and its activity in the left ventricle induced by renovascular hypertension. To examine the effect of CsA or perindopril on the cardiac hypertrophy, on the level of CaN mRNA expression, protein expression and its activity and the level of MAPK mRNA expression. To explore whether CaN activity is required for the long-term maintenance of cardiac pathologic responses and to discuss the possible mechanisms of CsA induced the regression of cardiac hypertrophy and to examine whether there is interconnectivity between CaN and mitogen-activated protein kinases.CONTENTS AND METHODS:1. The renovascular hypertension was induced by two kidney-one clip operation on the SD rats. Blood pressure was measured by tail -cuff methods and elimination the rats that blood pressure lower than 150 mmHg at four weeks after the operations. The drugs were given to the rats per day continued for one month from two months after the two kidney-one clip. We would investigate the changes: (1) The weight of left ventricle, the ratio of left ventricular weight to tibial length, thecross-sectional area of cardiac myocyte. The area was quantified using NIH image capture and quantitative analysis software. (2) The thickness of left ventricular posterior wall and interventricular septum, the ejection fraction (EF) and the p...