| Background:Heart failure can be defined as insufficient cardiac output to meet metabolic needs or sufficient cardiac output after compensatory neurohormone activation.Heart failure is a complex clinical syndrome characterized by a decline in the ability of the heart to pump blood and/or congestion.Heart failure is not a clinically independent disease.In recent years,the mechanism of the role of oxidative stress in the occurrence of heart failure has been extensively studied.Inappropriate increase in reactive oxygen species(ROS)is an important expression of the body’s oxidation/oxidation imbalance,and this mechanism plays an important role in the development of heart failure and in the treatment process.As one of the most important endogenous antioxidant stress pathways,the keapl-nrf2-are pathway occupies a popular position in the study of antioxidant field.Designing and developing the corresponding drugs to improve the body’s oxidative stress is an ideal way to treat heart failure and improve the myocardial function of patients.Establishing an economical and stable animal model of heart failure is an important prerequisite for normative research on the pathogenesis of heart failure and seeking effective treatment.Different methods were used to rebalance the oxidative/antioxidative imbalance in heart failure patients/animal models,thus reducing cardiac function damage and becoming a clinical breakthrough in the treatment of heart failure the treatment bottleneck and the important means to improve the prognosis.Studies have shown that isoproterenol makes the heart rate of rats accelerate,the myocardium continues to contract strongly,eventually causing heart failure.Intraperitoneal or subcutaneous injection of isoproterenol is a relatively noninvasive method,and the progressive and enzymatic changes of myocardial ischemia in rats induced by isoproterenol are similar to the lesions of acute myocardial infarction in humans.Ferulic acid is a common phenolic acid in plant tissues.The antioxidant mechanism of ferulic acid is complex and it is an effective regulating body oxidation/antioxidation level Heng’s traditional Chinese medicine extract.Purpose:To investigate the therapeutic effect and mechanism of ferulic acid in heart failure rat model.Methods:The rats were randomly divided into seven groups:control group(group A),ferulic acid group(group B),isoproterenol model group(group C)，ferulic acid low-dose therapy group(group D),ferulic acid medium-dose therapy group(group E),ferulic acid high-dose therapy group(group F)and ferulic acid combined nrf2 inhibitor group ml385(group G).The rats in C,D,E,F and G groups were injected subcutaneously with isoproterenol 3 mg/kg/d,saline in group A and ferulic acid in group B for 4 consecutive days.D,E Groups F and G were given gavage administration.The concentration of ferulic acid was 20 mg/kg/d in group D,40 mg/kg/d in group E,60 mg/kg/d in group F,40 mg/kg/d in group G and 10 mg/kg/d in group ML385.The rats in group A,B and C grew naturally without the behavior of gastric administration.(1)Left ventricular ejection fraction(LVEF)、Mean arterial pressure(MAP),left ventricular diastolic pressure(LVEDP)and left ventricular systolic blood pressure(L)were measured after 4 weeks of continuous administration.VSP,systolic left ventricular pressure increase rate(dp/dtmax)and diastolic left ventricular pressure decrease rate(-dp/dtmax);(2)detection of serum biochemical indexes of brain natriuretic peptide(BNP),endothelin-1(ET-1)and nitric oxide(NO);(3)determination of activity of SOD,glutathione peroxidase(GSH-Px)and malondialdehyde(MDA)in cardiac tissues;(4)detection of WBC-related proteins,caspase3 and Cleaved expression of aspase9.detection of levels of myoglobin mb(Ck-Mb),cardiac troponin i(cTnI),and lactate dehydrogenase(LDH);(5)WB detection of Nrf2 signaling pathway-related proteins(Nrf2,HO-1,and NQO1).Results:(1)After successful modeling,the model group compared with the blank control group:① LVEF(37.82±3.18 vs 52.15±4.31)decreased;LVSP(90.42±8.25 vs 125.33±5.74)decreased;+dp/dtmax(2419.84±297.12 vs 4640.28±449.28)decreased;-dp/dtmax(2667.24±314.08 vs 4274.41 ±409.33)decreased;MAP(94.21±9.16 vs 127.63±4.52)decreased;LVDP(13.37±1.65 vs 5.65±0.81)increased.② ALT(71.4±6.28 vs 72.7±8.31)and AST(120.5±9.86 vs 126.7±11.2)levels were not significantly changed.There were no significant changes in creatinine(18.46 ±1.234 vs 17.18 ±0.483),urea nitrogen(16.24±1.329 vs 15.33 ± 1.420)and urinary protein(9.994±0.842 vs 9.256±0.842).③ BNP level(4.659±0.041 vs 0.265±0.002)increased.④The level of ET-1(196.35±15.32 vs 101.51±5.34)increased and the level of NO(4.29±0.29 vs 16.37 ± 2.04)decreased.⑤SOD levels(41.55±4.98 vs 102.62±8.64)decreased;GSH-Px(62.19±6.97 vs 198.26±15.37)decreased;and MDA levels(1.525±0.12 vs 0.515±0.033)increased.⑥Caspase 3 mRNA was increased(4.352±0.261 vs 0.875±0.062),and Caspase 9 mRNA was increased(6.319±0.337 vs 0.943±0.051).Caspase 3 protein was increased(9.126± 1.002 vs 0.012 ±0.001).Caspase 9 protein was increased(11.25±1.118 vs 0.009±0.003).⑦CK-Mb(4.987±0.415 vs 1.000±0.000)increased;cTnI(2.954±0.264 vs 1.000±0.000)increased;and LDH(751.39±62.03 vs 243.42 ±21.36)increased.⑧ Nrf2 mRNA was decreased(0.218±0.009 vs 0.953 ± 0.008).HO-1 mRNA decreased(0.496±0.015 vs 1.259±0.015);NQO1 mRNA decreased(0.525±0.027 vs 1.112±0.028);Nrf2 protein decreased(0.435±0.041 vs 1.211±0.094);HO-1 protein decreased(0.517±0.043 vs 1.854±0.126);NQO1 protein decreased(0.342±0.031 vs 0.966±0.087).(2)The ferulic acid treatment group was compared with the model group after treatment with medium-dose avian acid:① LVEF(46.29±4.16 vs 37.82±3.18)increased;LVSP(101.35±8.46 vs 90.42±8.25)increased;+dp/dtmax(3287.14±258.46 vs 2419.84±297.12)increased;-dp/dtmax(3354.46±318.84 vs 2667.24±314.08)increased;MAP(108.34±8.46 vs 94.21±9.16)increased;LVDP(10.57±1.27 vs 13.37±1.65)decreased.② ALT(74.1 ±6.26 vs 71.4±6.28)and AST(119.5±10.9 vs 120.5±9.86)levels were not significantly changed.The levels of creatinine(20.85±1.954 vs 18.46±1.234),urea nitrogen(18.21±1.697 vs 16.24±1.329)and urinary protein(10.02±0.942 vs 9.994±0.842)were not significantly changed.③ BNP levels(2.158±0.016 vs 4.659±0.041)decreased.④ The level of ET-1(152.08±13.49 vs 196.35±15.32)decreased;the level of NO(8.06±0.61 vs 4.29±0.29)increased.⑤SOD levels(79.34±6.28 vs 41.55±4.98)increased;GSH-Px(108.19±9.52 vs 62.19±6.97)increased;and MDA levels(0.954±0.98 vs 1.525±0.12)decreased.⑥Caspase 3 mRNA(2.548±0.208 vs 4.352±0.261)decreased,and Caspase 9 mRNA(3.557±0.294 vs 6.319±0.337)decreased.Caspase 3(4.336±0.517 vs 9.126±1.002)decreased;Caspase 9(5.239±0.619 vs 11.25± 1.118)decreased⑦CK-Mb(2.943±0.328 vs 4.987±0.415)decreased;cTnI(1.328±0.813 vs 2.954±0.264)decreased;and LDH(318.96±26.11 vs 751.39±62.03)decreased.⑧Nrf2 mRNA was increased(0.517±0.029 vs 0.218±0.009).HO-1 mRNA was increased(0.799±0.065 vs 0.517±0.043);NQO1 mRNA was increased(0.572±0.044 vs 0.342 ±0.031);Nrf2 protein(0.801±0.072 vs 0.435±0.041)was increased;HO-1 protein was increased(0.799±0.065 vs 0.517±0.043).NQO1 protein was increased(0.572±0.044 vs 0.342±0.031).(3)After inhibition of Nrf2 inhibitors,compared with the medium-dose avian acid treatment group:①LVEF(41.38±3.53 vs 46.29±4.16)decreased;LVSP(91.26±7.31 vs 101.35±8.46)decreased;dp/dtmax(2516.37±266.34 vs 3287,14±258.46)decreased;-dp/dtmax(2684.34±155.59 vs 3354.46±318.84)decreased;MAP(98.26±6.47 vs 108.34±8.46)decreased;LVDP(13.28±1.94 vs 13.37±1.65)increased;.②ALT(72.9±5.46 vs 74.1±6.26)and AST(118.8±10.3 vs 119.5±10.9)levels were not significantly changed.There were no significant changes in creatinine(19.55 ±1.645 vs 22.46±2.016),urea nitrogen(15.22±1.634 vs 17.55±1.233)and urine protein(8.236±0.572 vs 10.02±0.942).③BNP level(2.954±0.017 vs 2.158±0.016)increased.④ The level of ET-1(182.31±14.73 vs 152.08± 13.49)increased;the level of NO(4.91±0.44 vs 8.06±0.61)decreased.⑤SOD level(45.31±4.27 vs 79.34±6.28)decreased,GSH-Px(71.33±7.91 vs 108.19 ± 9.52)decreased and MDA level(1.367±0.17 vs 0.954±0.98)increased.⑥Caspase 3 mRNA was increased(2.974±0.188 vs 2.974±0.188),and Caspase 9 mRNA was increased(4.166±0.396 vs 4.166±0.396).Increased Caspase 3(8.674±0.844 vs 4.336±0.517);Caspase 9(10.25±0.933 vs 5.239±0.619)increased⑦CK-Mb(4.693±0.520 vs 2.943±0.328)increased;cTnI(2.816±0.337 vs 1.328±0.813)increased;and LDH(708.35±52.15 vs 318.96±26.11)increased.⑧Nrf2 mRNA decreased(0.487±0.026 vs 0.801±0.072);HO-1 mRNA decreased(0.508±0.033 vs 0.799±0.065);NQO1 mRNA decreased(0.339±0.028 vs 0.572±0.044);Nrf2 protein decreased(0.487±0.026 vs 0.801 ±0.072);HO-1 protein decreased(0.508±0.033 vs 0.799±0.065);NQO1 protein decreased(0.339±0.028 vs 0.572±0.044).Conclusion:(1)Ferulic acid can effectively reduce isoproterenol-induced heart failure.(2)The mechanism of ferulic acid against heart failure is likely to be related to protecting cardiac diastolic function,inhibiting lipid peroxidation and reducing tissue apoptosis.(3)The protective effect of ferulic acid on isoproterenol-induced cardiac injury and its related mechanisms are correlated with the regulation of Nrf2 signaling pathway.(4)This study provides a strong scientific basis for the clinical application of ferulic acid in the treatment of heart failure and the protection of heart injury. |
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