Effects Of Testosterone On The Transcript Level Of Fas And SERCA2a In Postinfarction Heart Failure Male Rats' Myocardium

background and objectives:In the world, heart failure that seriously threatens to human health, is a common, costly, maimed disease with a high mortality, involving 2% adults . In the Framingham Heart Study , researchers found that the median survival time of male patients with congestive heart failure (CHF) was 1.7 years , and that of women patients was 3.2 years . The one-year survival rate for male and female patients were 57% and 64% seperately. In fact, the mortality of CHF patients was thrice as high as that of patients with chest cancer in three years. Patients with CHF have worse prognosis than most cancers ones .Heart failure is a disease causing cardiac dysfunction syndrome. Coronary artery disease (CAD) has become the first cause of CHF, involving 54% patients . Indeed, the CAD in the world, including China, is a common cause of CHF. Modern medical research shows: CHF is the terminal stage of "chain of cardiovascular events" , it causes hemodynamic, neuroendocrine and cytokines changes and leads to a vicious cycle. Despite a traditional digoxin , diuretic , combining ACEI and beta-blockers for heart failure treatment has been greatly improved the prognosis for CHF patients, still a lot had developed to the end-stage of heart failure . Stem cell transplantation has brought a lot hope to people, but current situation is not ideal. Few patients receive cardiac transplantation in clinic due to a smaller number of bodies. Heart failure has become an important cardiovascular syndrome that endangers human health. To further improve the prognosis of heart failure, people are trying to find new strategies.Testosterone, being used in the treatment of heart failure as a new strategy has been gained more and more attention in recent years. Testosterone as a hormone, can improve vascular elasticity; reduce myocardial ischemia; increase high-density lipoprotein, and lower low-density lipoprotein cholesterol; increase antithrombin-3 and fibrinolytic activity, strengthen muscle, inhibit inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α), reduce Q-T interval dispersion in patients with congestive heart failure, decrease serum cytokine levels, peripheral vascular resistance and heart load, increase cardiac index. Testosterone can regulate immune response. Supplementary testosterone may reduce pro-inflammatory cytokines such as TNF-αand interleukin-1, IL-10, increase anti-inflammatory cytokines. Based on the above findings, testosterone, as a new strategy for treatment of heart failure has been tremendous concerned.But its molecular mechanism is not clear.Fas also called APO-1, belonging to the member of tumor necrosis factor receptor super family, on the surface of many kinds of cells is inductively expressed . Fas molecule comprises 60-70 amino acids' conservative sequences which relate to cell death , called death domain. Fas is an important death receptor, and leads target cells apoptosis. The apoptosis of myocardial cells is conducted by Fas .Testosterone, as a growth hormone, has the physiological function of resisting to apoptosis, inducing prostate enlargement. It is not yet clear that anti-apoptotic role of Fas in the myocardium of patients with CHF.Measuring myocardial tissue mRNA expression of apoptosis-related genes Fas is benefical to understanding of the impact of testosterone. Researcher has found : in heart failure myocardium, membrane potential - dependent calcium channel expression of sarcoplasmic reticulum calcium release channels are decreased, peak systolic calcium flow is lowered. Clearance of cytosolic free calcium is mainly depend on the uptake of Ca²⁺ by the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a), while down-regulation of SERCA2a expression in failure myocardium causes lower clearance rate of Ca²⁺ in diastolic stage, leads to diastolic dysfunction. The impact of testosterone on Myocyte SERCA2a of patients with congestive heart failure is unknowed.Materials and Methods:120 healthy male rats, 3-month age, weight (290±40g), brought from the Experimental Animal Center of Henan, were randomly divided into two groups: sham operation group (Sham) (n = 15) and model group (n = 105). The rats in model group were ligated in the proximal left coronary artery.Six weeks later, left ventricular ejection fraction(LVEF) was assessed by 2-dimension ultrasoud. LVEF < 45% was consided as the success criteria for CHF. 44 rats with CHF were furthermore randomly divided into testosterone intervention group (CHF+TU n = 22) and CHF (n = 22). Medication: during 12 weeks of treatment intervention, CHF+TU group received deeply intramuscular injection of TU ( disolved in peanut oil ) 5mg/kg/times, once every 2 weeks (experimental doses were based on previous animals experiment) , and CHF group and the Sham group recived the same amount of sterile peanut oil. On the 19^th week, the rats were sacrificed to collect specimens and preserved in liquid nitrogen., the transcript level of Fas and SERCA2a in postinfarction heart failure male rats' myocardium was measured by RT-PCR (reverse transcription polymerase chain reaction). Statistical analysis of the data were obtained by using SPSS13.0 statistical software .Data comparion among groups were used by single-factor analysis of variance and q test.α= 0.05 level were taken as significance.Results :1 The levels of mRNA of Fas in CH+TU group were significantly lower than CHF group (0.535±0.041 vs. 0.570±0.060 P<0.05), still higher than Sham group (0.535±0.041 vs.0.431±0.056 P<0.05).2 the levels of mRNA of SERCA2a in CHF+TU group were higher than CHF group (0.516±0.075 vs.0.428±0.062 P<0.05 ),but lower than Sham group (0.516±0.075 vs.0.572±0.063 P<0.05).Conclusion:The increase of Fas mRNA level and the decline of SERCA2a mRNA are involved in the molecular mechanism of improving heart failure after testosterone replecement treatment.