| Research purposeSince heart failure (HF) becomes one of the important diseases which threat the health of contemporary old people gradually, the pathogenesis and developing mechanism of HF is widely researched and explored. The myocardial remodeling as one of the important mechanism of the occurrence and development of chronic heart failure is also increasingly concerned in recent years. The long-term myocardial hypertrophy is considered one of the important factors that cause heart failure occurring. New research indicates that the long time excessive activation of renin-angiotensin system (RAS) is participated in the mechanism of myocardial hypertrophy to failure. Its process is partially related to JAK-STAT pathway probably.JAK-STAT pathway is one of the acting pathway of interleukin 17 (IL-17), a former inflammatory cytokine. There is experiment indicating that myocardial hypertrophy and myocardial impairment can be reduced by inhibiting JAK-STAT pathway after heart failure occurred. However, different factors in this pathway activated effect opposite. STAT3 mainly play a role of inhibition of myocardial cell apoptosis. On the contrary, STAT1 can promote myocardial cell apoptosis. But they are activated in different time slightly. STAT3 is earlier activated than STAT1. Therefore, the heart failure model shall be established, and at the same time, antibody intervention shall be given in this experiment. It's in order to confirm the myocardial protection of STAT3 further, and explore whether the early application of IL-17 antibodies can influence the STAT3 level through obstructing the JAK-STAT pathway, and then inhibit its early myocardial endogenous protection in the early heart failure process.Research methodsExperimental animals: 20 male healthy Wistar rat, each weight is about (250±20) g, giving the conventional breeding. Randomization: A: Anti- IL17 Heart Failure group (n = 5); B: IgG Heart Failure group (n = 5); C: Heart Failure in control group (n = 5); D: The control group (n = 5). Adriamycin (ADR) inducing heart failure: give A, B and C three groups intraperitoneal injection of ADR made into 2mg/ml solution with physiological saline, dosing 8 times. On the 2, 4d inject ADR 1mg/kg.ip, on the 6, 8d inject ADR 2mg/kg.ip, on the 10, 12d inject ADR 3mg/kg.ip, on the 14, 16d inject ADR 4mg/kg.ip. The accumulative total is 20mg/kg.ip. Give group D injection of equal mass saline.Intervention are administered at the time: give group A intraperitoneal injection of rat IL - 17 antibody(100μg/0.8mlPBS); give group B intraperitoneal injection of the same type IgG1 (100μg/0.8mlPBS); give C,D two groups intraperitoneal injection of 0.8 ml PBS. All the above solutions are administered after ADR injection, eight times in all (0.1 ml/times).The behavior and signs observation, weight weighing and Ultrasonic Cardiogram are administered: ventricular septal thickness (IVST), left ventricular wall thickness (after LVPWT) and ejection fraction (EF) was measured and compared.After heart function test, remove the lung tissue, liver, kidney and heart. Make the lung tissue, liver and kidney into pathological slices and stained with HE, and observe their morphology changes. Use the analytical balance to take the quality of heart, and commutate heart weight index (HWI). Part of the organizations are made into pathological slices and stained with HE. Observe the myocardial pathological damage. The other organizations are freezing in - 80℃liquid nitrogen preservation rapidly. Then test p - STAT3 and t - STAT3 expression level with Western blot. Statistically analyse the result.ResultBehavior signs changes: CHF phenomenon appears obviously in the rats of A, B and C three groups, the rats of group D are in good condition.Weight changes: The weight of the rats in A, B two groups decrease obviously (p < 0.05). The weight of the rats in group C decline relatively, but there's no significant difference (p > 0.05).The weight of the rats in group D increase significantly (p < 0.05).In A, B and C three groups, terminal weight are obviously less than that in group D (p < 0.05), it's obviously less in group A than that in B, C two groups (p < 0.05), and there's no obvious difference between the B and C two groups (p > 0.05).Ultrasonic cardiogram result: IVST: It's significantly greater in A, B and C three groups than group D (p < 0.05). There's no obvious difference between the A, B and C three groups (p > 0.05). LVPWT: It's significantly greater in A, B and C three groups than group D (p < 0.05). There's no obvious difference between the A, B and C three groups (p > 0.05). EF: It's obviously less in A, B and C three groups than that in group D (p < 0.05), it's obviously less in group A than that in B, C two groups (p < 0.05), and there's no obvious difference between the B and C two groups (p > 0.05).HWI: It's significantly greater in A, B and C three groups than that in group D (p < 0.05). There's no obvious difference between the A, B and C three groups (p > 0.05). The pathological changes of myocardium, liver, lung and kidney: Myocardium:Apparent myocardial impairment appears in the rats in A, B and C three groups, more serious in group A. Lung: damage occurs in the rats in A, B and C three groups; it's more serious in group A. Liver: liver damage occurs in the rats in A, B and C three groups, there's no obvious difference between the three groups. Kidney: the four groups all perform mainly normal. Group D performs normal.p-STAT3: It expresses in A, B and C three groups more than group D significantly (p < 0.05). It expresses less in group A than that in the B and C two groups obviously (p < 0.05). It's less in group B than that in group C obviously (p < 0.05).t-STAT3: It expresses in A, B and C three groups more than group D significantly (p < 0.05). It's less obviously in group A than that in the B and C two groups (p < 0.05). There's no obvious difference between the B and C groups (p > 0.05).ConclusionApplication IL - 17 antibodies in early heart failure to inhibit JAK - STAT pathway can significantly reduce the level of STAT3's activation and expression. It weakens the myocardial endogenous protective role of STAT3. Consequently, IL - 17 can induce the production and activation of STAT3 in the myocardial tissue and also play a myocardial protective role appropriately in the very early heart failure. |
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