Effects Of Fosinopril On Myocardial Apoptosis And The Expression Of Fas/FasL Genes In Congestive Heart Failure Rats

Background and Purpose The transition from compensated ventricular hypertrophy to heart failure is associated with a marked reduction in myocyte mass and reduction in contractile force. The reduction in myocyte mass and the functional loss may be ascribed to the increased cell death by apoptosis, while the increased expression of Fas gene may accelerate the process. In this experiment, we investigated the changes of myocardial apoptosis and the expression of Fas and Fas ligand (FasL) genes in myocardium of rats with congestive heart failure, and studied the effects of fosinopril (angiotensin converting enzyme inhibitor, ACEI) on myocardial apoptosis and the expression of Fas and FasL genes of cardiomyocyte in experimental congestive heart failure rats. Methods Rat models were experimental hypertensive rats. Thirty Wistar-Kyoto rats were divided randomly into sham-operated group, operated group-left ventricular compensated hypertrophy group and operated group-congestive heart failure group. Terminal deoxynucleotidyl transferase- mediated dUTP nick end labeling (TUNEL) and ABC immunohistochemical staining were used respectively to detect the changes of apoptosis and protein expression of Fas and FasL genes, and mRNA expression of Fas gene was evaluated by RT-PCR analysis. After the model of chronic congestive heart failure was established by gradually constricting the abdominal aorta of Wistar-Kyoto rats, the animals were divided into heart failure group and fosinopril treated group. Another 10 rats were employed as control with sham-operated group. Hemodynamic parameters were determined, and changes of apoptosis and the expression of Fas and FasL genes were detected as well. Results The data showed that few apoptotic myocardial cells were found in sham-operated group, while apoptotic myocardial cells were found both in congestive heart failure group and compensated hypertrophy group. The number of apoptotic myocardial cells in congestive heart failure group increased significantly in comparison with that in compensated hypertrophy group (P<0.05). There was significant difference (P<0.05) in positive index (PI) of Fas protein, but no significant difference (P>0.05) in PI of FasL protein between sham-operated group and compensated hypertrophy group. When the congestive heart failure occurred, positive index (PI) of Fas and FasL protein in myocardial cells were increased very significantly (P<0.05) than those in myocardium of Wistar-Kyoto rats with compensated hypertrophy. The expression of Fas gene in myocardium of rats with congestive heart failure was significantly higher than that in sham-operated group and compensated hypertrophy group (P<0.05). Compared with sham-operated group, left ventricular end-diastolic pressure (LVEDP) in congestive heart failure group was increased (P<0.01), while ＋dp/dtmax and －dp/dtmax were decreased significantly (P<0.01). The LVEDP was lower but ＋dp/dtmax and －dp/dtmax were significantly higher in fosinopril treated group (P<0.01). The apoptosis index (AI) and the expression of Fas and FasL genes in fosinopril group were significantly lower than those in congestive heart failure group (P<0.01).Conclusions Increased myocardial apoptosis may be the important mechanism during the transition from compensated hypertrophy to heart failure in experimental congestive heart failure rats. Changes of myocardial apoptosis and the expression of Fas and FasL genes suggest that apoptosis and Fas/FasL system are involved in the experimental congestive heart failure rats. Fosinopril administration for a long time in case of chronic congestive heart failure may decrease the expression of Fas and FasL genes, and this can contribute to its role of reducing myocardial apoptosis and improve the myocardial function.