| Objective:To investigate the changes of calcium handling proteins [(Sarcoplasmic reticulum calcium adenodine triphosphatase,SERCA2a),(ryanodine receptor,RyR2),(phospholamban,PLB),(Na+-Ca2+exchanger, NCX1)]and inflammatory cytokines(TNF-α,IL-6,IL-1β)in rats with adriamycin-inducing dilated cardiomyopathy(DCM)and whether angiotensinⅡtype-1 receptor(AT-1)blocker,valsartan,has a protective effect by influencing calcium handling proteins and inflammatory cytokines.Methods:Models of DCM were established by adriamycin at a dose of 2mg/kg/W injected via intraperitonealy in Sprague-Dawley(SD)rats for 8 weeks.Rats were divided randomly into 3 groups as follows:control group(group C,n=10),DCM group(group M,n=11),and valsartan group (group V,n=10).Valsartan was administered by daily gavage at a dose of 30mg/kg/d in group V for 8 weeks.Physiological saline was administered in group C and group M.The left ventricular dimension at end-diastole (LVEDD)and at end-systole(LVESD),left ventricular ejection fraction (LVEF)were measured with echocardiography at the 9th week.Left ventricular systolic pressure(LVSP),left ventricular end-diastolic pressure(LVEDP),maximum left ventricular developed pressure increase rate(+LVdp/dtmax)and decrease rate(-LVdp/dtmax)were recorded with continuous physiological monitors.Concentrations of TNF-α,IL-6,IL-1βin serum were determined by method of radioimmunoassay. Ventricle weight and weight index[(left ventricular actual weight, LVAW),(right ventricular actual weight,RVAW),(left ventricular weight index,LVWI),(right ventricular weight index,RVWI)]were obtained. SERCA2a,RyR2,PLB,NCX1 mRNAs and proteins in cardiac muscle respectively were determined by methods of RT-PCR and Western blot. Histopathological characteristics of cardiac muscle were observed by HE and VG dyeing.Collagen volume fraction(CVF)was calculated.Results:1.Compared with group C,LVEDD and LVESD were significantly increased(both P＜0.05),and LVEF was reduced(P＜0.05)in adriamycin- induced cardiomyopathy rat models which were injected by adriamycin via intraperitonealy for 8 weeks.2.After valsartan treatment for 8 weeks,(1)Compared with group C,LVEDD was significantly increased[(7.1±0.4)vs(5.6±0.3)mm,P＜0.05],and LVEF was decreased [(77.1±2.0)vs(89.7±1.8)%,P＜0.05]in group M.In group V,LVEDD was(6.0±0.2)mm,which was significantly shorter than that in group M(P＜0.05),and LVEF was(86.0±1.2)%,which was higher than that in group M(P＜0.05).(2)LVSP in group M was lower than that in group C[(109.5±4.0)vs(131.8±1.7)mmHg,P＜0.05)].Compared with group C,±LVdp/dtmaxin group M were significantly decreased[(3679.5±260.0)vs (6241.7±237.3)mmHg/s and(-2748.9±240.0)vs(-5134.4±160.5)mmHg/s, both P＜0.05],and LVEDP in group M was increased[(21.2±1.2)vs (4.1±1.0)mmHg,P＜0.05)].In group V,LVSP was(115.5±3.5)mmHg, which was higher than that in group M(P＜0.05).±LVdp/dtmaxin group V respectively were(4837.2±237.8)mmHg/s,(-3722.8±167.2)mmHg/s, which were increased after valsartan treatment(both P＜0.05).Compared with group M,LVEDP was significantly reduced in group V[(13.2±1.0)mmHg,P＜0.05)].(3)Compared with group C,left ventricular weight(LVAW)and its index(LVWI)in group M were increased[(925.2±46.2)vs(736.6±26.5)mg and(2.24±0.21)vs(1.71±0.11),both P＜0.05]. These data in group V respectively were(790.5±30.7)mg and(1.87±0.14),which were significantly lower than those in group M(both P＜0.05).(4)Collagen volume fraction(CVF)in group M was significantly higher than that in group C[(13.79±1.14)%vs(1.91±0.22)%,P＜0.05].CVF of group V was(5.44±0.42)%,which was significantly attenuated after valsartan treatment(P＜0.05).(5)Compared with group C,mRNA levels of SERCA2a,RyR2 in group M were significantly decreased[(0.38±0.09)vs(0.75±0.10)and(0.36±0.07)vs(0.68±0.14),both P＜0.05],which were increased by valsartan treatment[(0.59±0.12)and(0.57±0.09),both P＜0.05].mRNA levels of PLB,NCX1 in group M were significantly higher than those in group C[(0.64±0.12)vs(0.30±0.09)and(0.58±0.11)vs(0.24±0.06),both P＜0.05].mRNA levels of PLB,NCX1 in group V respectively were(0.42±0.08)and(0.37±0.08),which were lower than those in group M both (P＜0.05).Similarly,protein levels of SERCA2a,RyR2 in group M were significantly decreased[(0.31±0.04)vs(0.69±0.07)and(0.29±0.09)vs(0.60±0.12),both P＜0.05],which were increased after valsartan treatment[(0.54±0.06)and(0.49±0.10),P＜0.05].Compared with group C,protein levels of PLB,NCX1 in group M were increased[(0.69±0.08)vs(0.36±0.06)and(0.68±0.10)vs(0.35±0.05),both P＜0.05]. After valsartan treatment in group V,protein level of NCX1 was significantly decreased[(0.44±0.07),P＜0.05],however,protein level of PLB did not differ significantly from that in group M[(0.65±0.11),P＞0.05].(6)Concentrations of TNF-α,IL-6,IL-1βin serum of group C respectively were 0 fmol/ml,(0.15±0.02)ng/ml,(0.12±0.02)ng/ml, these indexes in group M respectively were(20.31±1.98)fmol/ml,(0.31±0.03)ng/ml,(0.27±0.04)ng/ml,which were significantly higher than those in group C(both P＜0.05).Concentrations of these inflammatory cytokines in serum of group V respectively were(13.48±1.12)fmol/ml,(0.22±0.03)ng/ml,(0.17±0.02)ng/ml,which were attenuated by valsartan treatment(both P＜0.05).Conclusion:Treatment with angiotensinⅡtype-1 receptor(AT-1) blocker,valsartan,can attenuate ventricular remodeling and improve cardiac function by partly normalizing mRNA and protein levels of SERCA2a,RyR2,PLB,NCX1 in cardiac muscle and decreasing the expressions of TNF-α,IL-6,IL-1βin rats with dilated cardiomyopathy. |
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