| BackgroundCardiac hypertrophy(CH)is a kind of compensatory reaction which is produced by the pressure load or volume overload of the cardiac muscle cells in the long time.In a period of time,it can make myocardial cell hypertrophy and increase cardiomyocyte protein synthesis and proliferation of extracellular matrix to promote cardiac work.And it maintain the heart pumps blood and tissue blood supply.CH often occurs in pressure overload of the disease,such as high blood pressure,heart valve disease,etc.CH is an independent risk factor,which determines the prognosis of a variety of cardiovascular diseases.Therefore,it is essential to control the CH reversal of left ventricular hypertrophy in the development of the occurrence and the heart failure.Chrysanthemum(CM)is one kind of the chrysanthemum.It is classified as one of the eight famous Chinese medicine in Zhejiang province.CM has cardiovascular protection,lipid-lowering,hypoglycemic,antihypertensive,antioxidant,anticancer and hepatoprotective,neuroprotective and other pharmacological effects.In the field of cardiovascular disease treatment,researchers found that extract from Chrysanthemum Morifolium(CME)has a therapeutic effect on myocardial ischemia and arrhythmia.Notch is a highly conserved gene,which is expressed in various tissues of the heart and blood vessels.In recent years,the research of Notch signaling pathway in development and tumor has a large number of studies.In recent years,it has found that Notch is one of the basic signal pathways in the occurrence,development,pathology and physiology of the cardiovascular system.Studies show that the Notchl pathway can regulate the cell contact and affect the cell activity.Notch1 can activate the protective signal of the cardiac muscle tissue.Up-regulation of Notchl signaling pathway can aggravate oxidative stress injury.At present,few studies have involved the role of CM in the treatment of CH and its mechanism through the Notch signaling pathway.To further develop and rationally use this plant resource,the study was to elucidate the effect and underlying mechanism of CME on CH,and to study whether its mechanism is through the regulation of Notch1 signaling pathway to protect the heart muscle.ObjectiveIn the study,the CH model was established by subcutaneous injection of Isoproterenol(Iso)in rats,and to investigate whether CME plays a protective role by regulating the Notch1 signaling pathway.Methods40 clean grade Sprague-Dawley(SD)rats weighing 200g?250g,were randomly divided into 4 groups(n=10):Normal control group(s.c normal saline),CH model group(s.c Iso 5mg/kg/d),low-dose CME group(L-CME,s.c Iso 5mg/kg/d +ig.CME150mg/kg/d),high-dose CME group(H-CME,s.c Iso 5mg/kg/d +ig.CME600mg/kg/d).Normal control group and model group were given equal volume of normal saline.After 8 weeks of continuous subcutaneous injection and oral administration,the hemodynamic parameters were determined in each group.Detection of serum malondialdehyde(MDA)and total superoxide dismutase(T-SOD)activity in the carotid artery was detected;Cardiac mass index(HWI)and left ventricular mass index(LVWI)were calculated;glutathione peroxidase(GSH-PX)activity and nitric oxide(NO)level of myocardium were detected;the histological changes of myocardium and the degree of myocardial fibrosis of myocardial morphology HE staining and MASSON staining were observed;Immunohistochemical method was observed the expression of Notchl protein in myocardium of rats in each group.Results1.Hemodynamic changes? Left ventricular end diastolic pressure(LVEDP):model group>L-CME group>H-CME group>normal control group(9.88±1.02mmHgvs 7.60±1.15mmHg vs 6.77±1.29mmHg vs 5.49±0.94mmHg,;p<0.05).? Left ventricular systolic pressure(LVSP):normal control group>H-CME group>L-CME group>model group(140.45±9.84mmHgvs 120.36±16.71mmHg vs 111.72±12.89mmHgvs96.45±12.24mmHg,p<0.05).?Maximum rate of left ventricular pressure rise(+dp/dtmax):normal control group>H-CME group>L-CME group>model group(8569.23±973.32mmHg/s vs 6321.69± 1401.93mmHg/s vs;5897.65±1209.42 mmHg/s vs 4763.86± 1032.76 mmHg/s,p<0.05).? Maximum rate of left ventricular pressure descent(-dp/dtmax):normal control group>H-CME group>L-CME group>model group(8241,64± 1104.45mmHg/s vs 5975.57±1252.35mmHg/s vs 4965.43±1023.86mmHg/s vs 3963.65±987.73 mmHg/s,p<0.05).2.Heart wet weight/body weight(HWI)and Left ventricular wet weight/body weight(LVWI)? Heart wet weight/body weight(HWI):model group>L-CME group>H-CME group>normal control group(4.09±0.3 7mg/g vs 3.67±0.43mg/g vs 3.58±0.36mg/g vs 2.84±0.22 mg/g,p<0.05).? Left ventricular wet weight/body weight(LVWI):model group>L-CME group>H-CME group>normal control group(3.16±0.32 mg/gvs 2.84±0.25 mg/g vs 2.68±0.46 mg/g vs 2.36±0.24 mg/g,p<0.05)3.Blood biochemical index determination? MDA level:model group>L-CME group>H-CME group>normal control group(7.46±0.37 nmol/ml vs 6.31±0.49 nmol/ml vs 5.82±0.52 nmol/mlvs 4.24±0.26 nmol/ml,p<0.05)? T-SOD activity:normal control group>H-CME group>L-CME group>model group(332.44±25.69 U/ML vs 308.80± 11.77 U/ML vs 299.19± 10.75 U/ML vs 285.54±10.84 U/ML,p<0.05)4.Biochemical indexes of cardiac tissue? GSH-PX activity:normal control group>H-CME group>L-CME group>model group(853.76±54.78vs 798.56±78.64vs 763.45±67.34vs 643.31±86.23,p<0.05)? the level of NO:normal control group>H-CME group>L-CME group>model group(1.98±0.47?mol/gprot us 1.45±0.35?mol/gprot vs 1.38±0.31?mol/gprot vs 0.89±0.35?mol/gprot,p<0.05).5.Myocardial histopathology and immunohistochemistry.? HE staining:compared with the control group,the myocardial cell volume became larger,the cell arrangement was disordered,the cell gap increased,and there was a large number of cardiac muscle cell fiber hyperplasia in the model group.The drug delivery group was between the control group and the model group,and the high dose group was close to the control group.? Masson staining:compared with the control group,the model group of myocardial cells arranged in disorder.There are a large number of blue collagen fiber hyperplasia in the model group,the drug group is between the control group and model group,and high dose group were close to the control group.6.ImmunohistochemistryThe expressin of Notch 1 protein in left ventricle:model group>L-CME group>H-CME group>normal control group(0.456±0.054 vs 0.367±0.053 vs 0.282±0.035 vs 0.124±0.025,P<0.05)ConclusionNotch 1 signaling pathway has joined in Iso induced CH.CME has a protective effect on CH.And its mechanism may be related with inhibiting of Notchl signaling pathway,inhibiting cellular oxidative stress and increasing myocardial NO level. |
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