The Effect Of Proliferator-Activated Receptor-γ Agonst On Heart Function In Dilated Cardiomyopathy Rats And The Discussion On Its Mechanism

Objective:To observe the effect of peroxisome proliferatorsactivated receptor-γagonist Rosiglitazone on cardiac function and left ventricular remodeling in rats with adriamycin-inducing dilated cardiomyopathy(DCM)and discuss its mechanism from the perspective of inflammation,oxidative stress and apoptosis.Methods:1.The effect of peroxisome proliferators-activated receptor-γagonist Rosiglitazone on heart failure in rats with adriamycin-inducing dilated cardiomyopathy(DCM):Sprague-Dawley rats were randomly divided into 3 groups as follows: control group(group C,n=10),DCM group(group D,n=10)and Rosiglitazone group(group D+R,n=10).To establish adriamycin-induced cardiomyopathy rat models by intraperitoneal injection of adriamycin (2mg/kg/w)for 8 weeks.Rosiglitazone was administered by daily gavage at a dose of 3mg/kg/d in group D+R for 8 weeks.At the 19th week,left ventricular dimension at end-diastole(LVEDD)and left ventricular ejection fraction(LVEF)were measured with echocardiography. Maximum left ventricular developed pressure increase rate(+LVdp/dtmax) and decrease rate(-LVdp/dtmin)were recorded with continuous physiological monitors.Histopathological characteristics of cardiac muscle were observed by HE and VG dyeing.Collagen volume fraction(CVF)was calculated.2.The effect of PPAR-γagonist Rosiglitazone pretreatment on rats with adriamycin-inducing dilated cardiomyopathy(DCM):Sprague-Dawley rats were randomly divided into 3 groups as follows: control group(group C_P,n=10),DCM group(group D_P,n=10)and Rosiglitazone group(group D+R_P,n=10).To establish adriamycin-induced cardiomyopathy rat models by intraperitoneal injection of adriamycin (2mg/kg/w)for 8 weeks.Rosiglitazone(3mg/kg/d)was infused at 4 weeks before the first injection of adriamycin until the 14th week.At the 15th week,LVEDD and LVEF were measured with echocardiography. +LVdp/dtmax and -LVdp/dtmin were recorded with continuous physiological monitors.Left ventricular weight index(LVWI)and right ventricular weight index(RVWI)were obtained.Histopathological characteristics of cardiac muscle were observed by HE and VG dyeing. Collagen volume fraction(CVF)was calculated.PPAR_γmRNA in myocardium was determined by method of RT-PCR.Concentration of TNF-α,IL-6,IL-1βin serum and myocardium were determined by method of radioimmunoassay.The myocardial total antioxidation capacity(TAOC) and concentration of malondialdehyde(MDA)in myocardium were measured with colorimetric analysis.The expression of Bax,Bcl-2,Fas,Fas-L proteins in myocardium were determined by method of Western blot. Results:1.The effect of PPAR-γagonist Rosiglitazone on heart failure in rats with adriamycin-inducing DCM:(1)To Compared D+R group with D group,there was no significantly difference in LVEDD[(7.2±0.4)mm vs(6.9±0.2)mm,P＞0.05],LVEF[(76.0±1.6)%vs(75.6±2.5)%,P＞0.05)],+LVdp/dtmax [(3631.41±273.9)mmHg/s vs(3551.5±256.4)mmHg/s,P＞0.05], -LVdp/dtmax[-(2808.2±197.4)mmHg/s vs-(2785.8±215.0)mmHg/s, P＞0.05].(2)To Compared group D+R with group D,there was no significantly difference in necrosis degree of myocardium and CVF [(12.08±0.93)%vs(11.78±0.62)%,P＞0.05].2.The effect of PPAR-γagonist Rosiglitazone pretreatment on rats with adriamycin-inducing dilated cardiomyopathy(DCM):(1)Heart function:LVEDD was lower in group D+R_P than that in group D_P[(6.3±0.3)mm vs(6.9±0.4)mm,P＜0.05],and higher in group D+R_P than that in group C_P[(6.3±0.3)mm vs(5.55±0.4)mm,P＜0.05]; LVEF was higher in group D+R_P than that in group D_P[(84.8±1.7)%vs (78.0±2.2)%,P＜0.05],and lower in group D+R_P than that in group C_P [(84.8±1.7)%vs(90.3±1.3)%,P＜0.05];+dp/dtmax was higher in group D+R_P than that in group D_P[(4557.1±285.7)mmHg/s vs(3488.1±470.6) mmHg/s,P＜0.05],and lower in group D+R_P than that in group C_P[(4557.1±285.7)mmHg/s vs(6045.4±205.0)mmHg/s,P＜0.05]; -dp/dtmaxas was higher in group D+R_P than that in group D_P[-(3291.6±261.5)mmHg/s vs -(2722.8±201.4)mmHg/s,P＜0.05],and lower in group D+R_P than that in group C_P[-(3291.6±261.5)mmHg/s vs -(5137.2±183.8)mmHg/s,P＜0.05].(2)Histopathological characteristics:Necrosis degree of myocardium was serious in group D_P.Necrosis degree of myocardium was improved in group D+R_P..CVF was lower in group D+R_P than that in group D_P[(6.91±0.5)%vs(11.55±1.1)%,P＜0.05],and higher in group D+R_P than that in group C_P[(6.91±0.5)%vs(2.68±0.5)%,P＜0.05]. LVWI and RVWI were both lower in group D+R_P than that in group D_P[(2.00±0.14 vs 2.43±0.11,P＜0.05;(0.63±0.04 vs 0.77±0.03, P＜0.05)],and higher in group D+R_P than that in group C_P[(2.00±0.14 vs 1.73±0.06,P＜0.05);(0.63±0.04 vs 0.40±0.04,P＜0.05)](3)Expression of PPAR_γmRNA:Expression of PPAR_γmRNA in myocardium was higher in group D+R_P than that in group D_P(0.65±0.03 vs 0.34±0.03,P＜0.05),and lower in group D+R_P than that in group C_P(0.65±0.03 vs 0.92±0.05,P＜0.05).(4)Inflammation factors:Compared with group D_P,concentration of TNF-α,IL-6,IL-1βin serum and myocardium were lower in group D+ R_P.[(12.74±1.76)fmol/ml vs(20.51±2.02)fmol/ml,P＜0.05;(20.51±1.67) pg/mgprot vs(43.53±2.09)pg/mgprot,P＜0.05],[(0.23±0.03)ng/ml vs (0.32±0.02)ng/ml,P＜0.05;(11.67±0.88)pg/mgprot vs(17.39±1.58) pg/mgprot,P＜0.05],[(0.17±0.04)ng/ml vs(0.25±0.04)ng/ml,P＜0.05; (8.50±1.87)pg/mgprot vs(11.64±1.20)pg/mgprot,P＜0.05].Compared with group C_P,concentration of TNF-α,IL-6,IL-1βin serum and myocardium were higher in group D+R_P:[(12.74±1.76)fmol/ml vs (0)fmol/ml,P＜0.05;(20.51±1.67)pg/mgprot vs(2.25±2.91)fmol/ml, P＜0.05],[(0.23±0.03)ng/ml vs(0.15±0.04)ng/ml,P＜0.05;(11.67±0.88) pg/mgprot vs(1.57±1.73 pg/mgprot,P＜0.05)],[(0.17±0.04)ng/ml vs (0.11±0.06)ng/ml,P＜0.05;(8.50±1.87)pg/mgprot vs(3.08±3.27) pg/mgprot,P＜0.05].(5).oxidative stress:Compared with group D_P,T-AOC in group D+ R_P was improved[(1.37±0.20)U/mgprot vs(1.06±0.16)U/mgprot, P＜0.05],MDA in myocardium was decreased[(3.63±0.68)nmol/mgprot vs(5.63±0.66)nmol/mgprot,P＜0.05].Compared with group C_P,T-AOC in group D+R_P was decreased[(1.37±0.20)U/mgprot vs(1.69±0.19 U/mgprot,P＜0.05],MDA in myocardium was increased[(3.63±0.68) nmol/mgprot vs(2.19±0.42)nmol/mgprot,P＜0.05].(6).Apoptosis:Compare group D+R_P with group D_P,Bcl-2 was higher(0.36±0.05 vs 0.23±0.03,P＜0.05),Bax was lower(0.34±0.06 vs 0.62±0.07,P＜0.05),Fas was lower(0.32±0.06 vs 0.48±0.05,P＜0.05)and Fas-L was lower too(0.24±0.03 vs 0.51±0.08,P＜0.05).Compare group D+R_P with group C_P.Bcl-2 was lower(0.36±0.05 vs 0.53±0.05,P＜0.05), Bax was higher(0.34±0.06 vs 0.18±0.03,P＜0.05),Fas was higher(0.32±0.06 vs 0.12±0.04,P＜0.05)and Fas-L was higher(0.24±0.03 vs 0.14±0.02,P＜0.05).Conclusion:PPAR-γagonist Rosiglitazone has no effect on heart function and left ventricular remodeling in rats with heart failure which reduced by dilated cardiomyopathy(DCM).But pretrement with PPAR-γ,agonist Rosiglitazone can lighten the degree of heart failure in rats which reduced by DCM.To inhibit inflammation cytokines in serum and myocardium, enhance antioxidative ability in myocardium and regulation some protein of apoptosis may be its mechanism.