Evaluating The Effects Of ACEI, AT₁RA On LVRM In Rats With Myocardial Infarction And The Partial Mechanism--Roles Of CT-1, Gp130, AN, Hsp56

Objective Left ventricular remodeling (LVRM) after myocardial infarction (MI) is the important predictor factor for cardiac dysfunction. How to effectively attenuate LVRM has been the focus of clinical study. It was shown recently that the renin-angiotensin system (RAS), especially myocardial RAS plays an important role in LVRM. Angiotensin converting enzyme inhibitor (ACEI), angiotensin II type 1 receptor antagonist (AT1RA) have shown good prospect by inhibiting RAS at different part. However, the mechanism of them have not been elucidated. Both of them have advantages and disadvantages. Therefore, there are trend to use in combination with them in recent years. Recently, the role of cytokine in LVRM gain great attention. Cardiotrophin-1(CT-1), a newly isolated member of the IL-6-related cytokine family, being the most potent factor in IL-6 family inducing myocardial hypertrophy in vitro. CT-1, via coupling through the receptor gp130/LIFR has been shown to activate a number of signalling pathways in cardiac myocytes inducing LVRM. Furthermore, CT-1 can upregulate myocardial hypertrophin-related genes such as Angiotensinogen(AN), heat shock protein 56 (hsp56). It has been newly shown that there are additive effect between CT-1 and AngII in inducing myocardial hepretrophy in vitro,which indicating there being important cross-talk between G-protein coupled receptor and cytokine, which open new avenues for effectively attenuating LVRM. However, little is known about the role of CT-1 in LVRM after MI. Whether the benefical effect of RAS inhibitors on LVRM is partial related to the down-regulation of CT-1 and related genes by inhibiting the effect of AngII. Therefore, this study was designed to compare the effects of ACEI, AT1RA and combination thrapy on LVRM, CT-1 signalling pathway as well as related genes with LVRM in rats with MI, to futher study molecular mechanism of LVRM and guide clinical practice.Methods The rat model of MI was produced by ligating left anterior decending coronary artery. Survivors were randomly divided into 2 groups at 24 hours after MI: MI group and drug group, the former was subdivided into 5 groups according to time at 1, 3, 7,14,28 days after MI while the latter being enalapril(10mg·kg-1·d-1)(E)group, losartan(20mg·kg-1·d-1)(L)group and combination of enalapril and losartan(5mg·kg-1·d-1and 10mg·kg-1·d-1)(E/L)group, drug was delivered by direct gastric gavage for 4 weeks beginning at the 2nd after MI. Sham (S) group were selected randomly to serve as controls. Researches were done as follows: (1) the hemodynamics was measured by catheter measuring. (2) LVRM was evaluated by pathologic analysis. (3) Myocardial hydroproline content (HC) in LV infarcted (IZ) and non-infarcted zone (NIZ) were measured by chloramine T method.(4)plasma AngII, ALD and myocardial AngII were determined by radioimmunoassay method.(5)The mRNA levels of CT-1, gp130, AN, hsp56 in IZ and NIZ were measured by RT-PCR.(6)The protein level of gp130 in IZ and NIZ were detected byimmunohistochemistry and Western-blot respectively.Results(1) AMI resulted in significant increase in ventricular weight, while were significantly decreased in three drug groups (P<0.05~0.001). Furthermore, heart weight index (HWI) and left ventricular weight index (LVWI) were decreased most remarkably in E/L group (P<0.01~0.001).(2)HC was progressively elevated at 3 days after MI(P<0.01~0.001) while significantly decreased in three drug groups (P<0.01~0.001). Comparing with MI group. NIZ HC decreased the mostly in E group.(3) Plasma AngII,ALD as well as myocardial AngII were elevated in MI group and sustained 28 days which were greatly depressed in E and E/L group (P<0.05~0.01).Increased in plasma AngII, ALD as well as IZ AngII (P<0.05~0.001) while decreased in NIZ AngII (P<0.05) were found in L group. (4) Correlative analysis revealed that LVWI,HC were significant positive correlated with myocardial AngII (r1=0.861, r2=0.774),not being related with plasma AngII,ALD...