An Initial Study Of ACE And ACE2 Expression In Ventricular Of Adult S-D Rats Under Hypoxia Simulated To High Altitude And Its Possible Mechanism

Background: High altitude heart disease is one of frequently encountered diseases in high altitude area, researches about its generating mechanism have positive sense to plateau dweller undoubtly. Hypopiesis and hypoxia environment may induce myocardial remodeling represented by myocadial hypertrophy and corresponding alteration of pumping function mostly happened in right ventricular. This kind of cardiac remodeling led by hypoxia is major patho-foundation of high altitude disease, and research about this myocardial remodeling is vital to the understanding of high altitude heart diseases.Renin-angiotensin-aldosterone system (RAS) is an important endocrine system in vivo. Its primary effector molecule angiotensinâ…¡can induce myocardium hypertrophy,cardiac fibrosis and lead considerable role in cardiac remodeling and alteration of cardiac function. It has been presumed previously that angiotensin convertion enzyme (ACE) is only the key enzyme regulate Angâ…¡in RAS , until the discovery of ACE2.ACE2 is only one homlog of ACE, express moderatly in heart. It is considered that the major function of ACE2 is hydrolysis Angâ…¡to Ang1-7, and regulate the level of several peptides such as Angâ…¡and Ang1-7 together with ACE. Now it is considered that ACE2 is a protective factor in myocardial, can attenuate myocardiac remodeling led by many heart diseases such as hypertension,diabete,dilated cardiomyopathy,myocardial infarction and so on, and correlated significantly with cardiac remodeling and alteration of cardiac function. The research about hypoxia show: ACE2 gene knock-out resulted in up-regulation of hypoxia induced genes BNIP3 and PAI-1 expression in myocardial tissue;Myocardial infarct may induce ACE2 up-regulation in heart of human and murine; ACE2 may attenuate hypoxia induced cardiac fibroblast activation either; Demonstrated that ACE2 may play important role in adaptive changes of heart under plateau hypoxia environment. And the relative research is absent now.Objective: The goal of this study was to investigate the changing pattern of ACE and ACE2 expression in murine heart under hypoxic environment simulated to plateau(5000m,23h/d). Then explore impact of hypoxia environment combined with captopril to the activity of ACE2 in heart. And try to detect the relationship between ACE2 and myocardial remodeling induced by hypoxia environment.Methods:1. For detection of ACE and ACE2 expression, adult S-D rats were raised under hypoxia environment simulated to altitude of 5000 m (23h/d) for 1 or 30 d. For determination of enzymes activity, adult S-D rats were raised under hypoxia environment simulated to altitude of 5000 m (23h/d) for 30 d with captopril or distilled water intragastric administration. Control group were raised in normoxic air condition respectively. All groups were raised in the same food and drink condition.2. To explore the effects of hypoxia on the myocardiac architecture and function:â‘ The index of ventricular mass and cardiac function of double ventriculars was measured firstly.â‘¡The changes of collagen mRNA expression was determined by RT-PCR;â‘¢The changes of collagen protein synthesis were determined by measuring the hydroxyproline cotent of myocardium;â‘£The shape of myocardium and distribution of collagen was investigated by HE and red-sinus dyeing;3. To analyze the changes of ACE and ACE2 expression level:â‘ The expression of ACE and ACE2 was examined by RT-PCR and Western blotting;â‘¡The distributon of ACE and ACE2 were determined by double labeling of immunofluorescence.â‘¢Angâ…¡content in double ventricular was determined by radioactivity immunization.â‘£ACE and ACE2 activity were determined by fluence substrate mca-YVDAPK-Dnp.Results:1. Myocardial architecture and cardiac function were changed obviously under hypoxic environment simulated to 5000 m high altitude, expressed by upregulation of right ventricular function,hypertrophy and myofibrosis. Compare to placebo group, captopril attenuated myocardial remodeling led by hypoxia dramatically.2. ACE and ACE2 mRNA and protein expression was increased markedly in the both ventricular under chronic hypoxia group. On the protein level, there was significant deviation of ACE and ACE2 between the left and right ventricular in chronic hypoxia group,displayed by dramatic increase of ACE in right ventricular and ACE2 in the left. Angâ…¡content increase dramatically in right ventricular of chronic hypoxia group.3. ACE and ACE2 activity was increased significantly in the both ventriculars under chronic hypoxia group. Captopril administration had no significant influence on the upregulation of ACE2 activity in right ventricular, and inhibit the increase of ACE2 activity in left ventricular and ACE activity in double ventricular dramatically.Conclusion:together higher ACE and ACE2 expression was observed in both ventricular of adult S-D rats exposed to chronic hypoxia environment simulated to 5000 m altitude plateau. There was significant variable expression between left and right ventricular especially in protein level of hypoxia group, this change maybe relevant with up-regulation of Angâ…¡content in right ventricular and the formation of myocardial remodeling in plateau environment. There was still high level of ACE2 activity in right ventricular of chronic hypoxia group accepted captopril administration, indicate alteration of ACE2 level maybe participate in anti-cardiac damage action led by ACE inhibitor.