Experimental Study On The Effect Of Apoptosis And Bcl-2, Bax Expression In Failing Myocardium With Enalapril In Rats

Objective In recent years, More and more studies focus on the pole of cardiomyocyte apoptosis in myocardial remodeling. It is most likely that cardiomyocyte-specific apoptosis is the key of the progressive transition from non-heart-failure to heart failure(HF). Myocardial remodeling is the molecule biological basis of the development of HF . Apoptosis has been shown to contribute to progressive decline in left ventricular function, and congestive heart failure. But the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood. And the mechanisms by which angiotensin-converting enzyme (ACE) inhibitor modulates apoptosis in HF are unclear. Therefore, we examined the impact of ACE inhibitor with enalapril on myocardial remodeling, apoptosis, anti-apoptotic Bcl-2and pro-apoptotic Bax protein expression in chronic pressure overload HF in rats. We aimed at mechanisms responsible for HF and offerred to the theory of clinic basal therapeutic modalities.Methods The rat model of chronic pressure overload HF was induced by transverse abdominal aortic constriction. 30 rats were randomized to 6 weeks of therapy with enalapril (Ena, 10 mg daily, n = 10) or to no therapy (HF, n =12) or to sham operation without constriction at all (control, n=8). The CHF rat model was established by constriction for 6 weeks.After 3 months of study. These rats were killed after measurement of haemodynamic parameters and the hearts removed. The left and right ventricles were dissected and weighed separately. The part of LV free wall was stored in formalin, dehydrated in ethanol, and paraffin embedded for TUNEL staining and immunohistochemistry. Another part was snap frozen in liquid nitrogen, and stored at -80 C for Western blot. Presence of nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed using the immunohistochemical deoxynucleotidal transferase-mediated dUTP- digoxigenin nick-end labeling (TUNEL) method. The monitoring of proapoptotic Bax, and antiapoptotic Bcl-2 genes was determined by Western blot and immunohistochemistry.Result In CHF rats, there was significant (P < 0.01) systolic dysfunction compared to sham. Myocardial apoptosis was significantly increased (P <0.01). The expression ofBcl-2, an inhibitor of apoptosis, was significantly reduced and the Bcl-2 to Bax ratio reduced. Bax were significantly elevated in heart failure rats. Immunohistochemistry confirmed increased Bax staining in failing myocardium, with reduced Bcl-2. Enalapril treatment resulted in: (1) improved LV remodeling (P< 0.05), (2) reduced myocardial apoptosis (P < 0.01), and (3) selective reduction in myocardial Bcl-2expression (P < 0.05) with increased Bax expression.Conclusion These data suggest that adrenergic activation, such as occurs in chronic pressure overload HF, increases cardiomyocyte-specific apoptosis and Bax expression and reduced Bcl-2 and the Bcl-2 to Bax ratio. ACE inhibitor in HF reduces myocardial apoptosis; prevented the changes of Bcl-2 and Bax, may be one mechanism of preventing the progression of left ventricular dysfunction.