| Background and purpose :1.To explore the expression of peroxisome proliferator-activated receptor γcoactivator 1a(Peroxisome Proliferator-Activated Receptor γ Coactivator 1α,PGC1α)in physiological and pathological cardiac hypertrophy,and to elucidate the role of pgc1α in this process.2.Through activating the oxidation of fatty acids in heart to reduce the pathological myocardial hypertrophy.Methods:1.Abdominal Aortic Constriction(AAC)was performed to simulate the pressure overload induced cardiac hypertrophy.C57 mice were divided into 2 groups,sham group(sham)and operation group(AAC),8 mice in each group.The mice were dissected 28 days after operation,and the hearts were taken out,weighed and photographed.The upper 1/3 of the hearts were fixed and embedded,and the left ventricular tissues were taken for molecular experiments.Take a small piece of heart tissue,extract protein,detect its fibrosis index and heart failure related index;RNA was extracted from another small piece of heart tissue,and the gene expression of fibrosis and heart failure was detected.The heart tissues were embedded in paraffin and stained for fibrosis.2.The model of physiological cardiac hypertrophy was established by 21-day high-intensity swimming in mice.The experiment was divided into two groups: sham group and swim-21 day group,with 8 C57 mice in each group.After 21 days,the mice were dissected,and the hearts were taken out,weighed and photographed.The upper 1/3 of the hearts were fixed and embedded,and the left ventricular myocardium was taken for molecular experiments.Take a small piece of heart tissue,extract protein,detect its fibrosis index and heart failure related index;RNA was extracted from another small piece of heart tissue,and the gene expression of fibrosis and heart failure was detected.The heart tissues were embedded in paraffin and stained for fibrosis.3.Comparison of pathological myocardial hypertrophy and physiological myocardial hypertrophy.The experiment was divided into three groups: sham group,swim-21 day group,AAC-7 day group,8 C57 mice in each group.After 21 days,the mice were killed,and the hearts were taken out,weighed and photographed.The left ventricular myocardium was taken for molecular experiments.A small piece of heart tissue was taken,protein was extracted,and the levels of PGC1α and heart failure markers were detected.Another small piece of heart tissue was taken to extract RNA,and the m RNA expression levels of PGC1α,fatty acid oxidation,myocardial fibrosis and heart failure related genes were detected.RNA sequencing was performed to analyze differential genes.4.Activation of PPARα by fenofibrate promotes fatty acid oxidation in pathological cardiac hypertrophy.The experiment was divided into two groups:AAC-28 day group,AAC+ fenofibrate group.The mice were pretreated with fenofibrate diet for 3 days,and then abdominal aortic coarctation was performed.After 28 days,the mice were dissected,and the hearts were taken out,weighed and photographed.The upper 1/3 of the hearts were taken for fixed embedding,and the left ventricular myocardium was taken for molecular experiments.Collect left ventricular tissue,take a small piece of heart tissue,extract protein,detect the level of heart failure markers;Another small piece of heart tissue was taken to extract RNA,and the expression level of myocardial fibrosis and cardiac hypertrophy related m RNA was detected.The heart tissues were embedded in paraffin and stained for fibrosis.5.Inhibition of AKT with MK2206.The experiment was divided into three groups: Sham Group,AAC-4 Day Group,AAC + MK2206 Group.After one day of preconditioning,the mice underwent abdominal Coarctation of the aorta.Four days later,the hearts were dissected and weighed.The left ventricular muscle was harvested for pgc1α levels,heart failure markers and fibrosis markersResults:The abdominal Coarctation of the aorta increased the cardiac afterload in mice,which led to pathological hypertrophy of the myocardium,accompanied by heart failure and interstitial fibrosis.(1)the heart/body weight ratio of AAC28-DAY-OLD mice was significantly higher than that of sham group(p < 0.05).(2)the expression of FN1,COL3A1,COL1A2 and NPPA,NPPB were significantly up-regulated(p < 0.05).(3)FN1 and BNP were significantly up-regulated at protein level in AAC28-DAY-OLD mice(p < 0.05).(4)Area of cardiac fibrosis in AAC28-DAY-OLD mice was significantly more than that in sham group.2.High intensity swimming(swim)can induce physiological myocardial hypertrophy(1)compared with Sham Group,the heart/body weight ratio of SWIM-21-day-old mice increased(p < 0.05).(2)there were no significant changes in the fibrosis genes FN1,COL3A1,COL1A2,ANP and BNP in SWIM-21-day-old mice compared with sham group(P >0.05).(3)compared with sham group,there were no significant differences in protein levels of FN1,COL1A2 and BNP in SWIM-21-day-old mice.(4)there was no difference in cardiac fibrosis between Sham Group and Swim-21 day group.3.Comparison of physiological and pathological myocardial hypertrophy(1)there was no difference in heart/body weight ratio between swim-21 day group and AAC-7 group(P > 0.05),but it was higher than that of sham group(p <0.05).(2)compared with sham group,PGC1 α and fatty acid oxidation genes were significantly up-regulated in SWIM-21-day group(p < 0.05),while PGC1 α and fatty acid oxidation genes were significantly down-regulated in AAC-7 group(p < 0.05).(3)compared with sham group,PGC1 α protein in SWIM-21 group was significantly increased and BNP protein level in heart failure index was slightly increased(p < 0.05),while PGC1 α protein in AAC-7 group was significantly decreased(p < 0.05),the level of BNP protein was significantly increased in patients with heart failure(P < 0.05).4.PPAR α agonist fenofibrate can reduce pathological myocardial hypertrophy.(1)the heart-to-body weight ratio in AAC + fenofibrate group was significantly lower than that in AAC 28-day group(p < 0.05).(2)the FN1 and COL1 levels in the fenofibrate treatment group were significantly lower than those in the AAC 28-day group(p < 0.05).(3)the m RNA expression levels of FN1 and COL1 genes in AAC + fenofibrate treatment group were significantly lower than those in AAC 28-day group(p < 0.05),and the gene expression levels of fatty acid oxidation were significantly higher than those in AAC 28-day group(p < 0.05),the m RNA expression levels of ANP and BNP genes were significantly lower than those in AAC28 group(p < 0.05).(4)the area of fibrosis in the AAC + fenofibrate group was significantly lower than that in the AAC 28-day group.5.MK2206 can inhibit AKT to activate PGC1α and reduce heart failure.(1)Heart/body weight ratio was lower in MK2206 group than in AAC group.(2)The expression of PGC1α in MK2206 group was higher than that in AAC group.(3)The markers of heart failure and fibrosis were down-regulated in MK2206 group.Conclusion:1.PGC1α is down-regulated and fatty acid oxidation ability is weakened in pathological cardiac hypertrophy.In physiological cardiac hypertrophy,PGC1α is upregulated and fatty acid oxidation capacity is upregulated.2.Early application of PPARα agonist fenofibrate can reduce the progression of pathological cardiac hypertrophy.3.The down-regulation of PGC1 a in pathological cardiac hypertrophy may be related to the abnormal activation of AKT-related pathways... |
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