Disruption of natural healing process in autoimmune myocarditis and progression to dilated cardiomyopathy

自身免疫性心肌炎自然愈合过程的破坏和扩张型心肌病的进展

• 批准号: 12670653
• 负责人: HANAWA Haruo
• 金额: $ 2.05万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670653/
• 关键词: autoimmune myocarditis; gene therapy; gene expression; dilated cardiomyopathy; MCP-1; IL-10; endothelin; βblocker; オステオポンチン; 心筋炎; 自己免疫疾患; サイトカイン; ケモカイン

(1) Marker in myocarditisElevation of sFas and sFasL levels at initial presentation appear to be a good serological marker to predict the prognosis of acute myocarditis. MCP-1 may play an important role in the pathogenesis of human acute myocarditis as well as in the progression of rat Experimental autoimmune myocarditis (EAM). Serum IL-10 levels may play a role m evaluation of the disease activity in patients with cardiac sarcoidosis.(2) Therapy for myocarditisA low dose of carvedilol has beneficial effects on rat dilated cardiomyopathy The area of myocardial fibrosis in chronic phase of Experimental autoimmune myocarditis was markedly reduced by quinapril. Bisoprolol improved survival independently, of its effect on left ventricular function by reducing sudden death in EAM. The prevention of EAM by administering the anti-CD 2 monoclonal antibody resulted from T cell depletion during theinduction phase,(3) Gene therapy for EAMGene transfer into muscle by electroporation in vivo is an … More effective means of delivery of IL-10, INFγ receptor-IgG, secretary leukocyte protease inhibitor-IgG and CTLA4-IgG for the treatment of autoimmune myocarditis.(4) Time Course of Gene Expression in EAMα-cardiac myosin showed a 26-fold decrease and β-cardiac myosm a 3.9-fold increase at day 14. ANP and BNP increased 48- and 6.4-fold respectively at day 21 and 14. AT1 receptor, ACE and ET1 increased 22- at day 21, 6.3- at day 21 and 17-fold, respectively at day 14. Aldosterone receptor decreased 2.2-fold at day 14, but aldsterone synthethase was detected only at day 14 and 21. Interleukin (IL) -2, IL-10, interferon-γ and monocyte chemoattractant protein-1 increased 9.1- at day 14, 398- at day 21, 43- at day 14 and 142-fold at day 14, respectively. Collagen type 3, Collagen type 1 and fibronectin increased 35-, 1.7- and 45- fold at day 21. Interestingly, osteopontin showed a 4542-fold increase and it was the higtest mRNA of all at day 14.Isoform of cardiac myosin and NP are dramatically changed in EAM. RAA and ET expressions are changed diversely in EAM time course. Cytokine, chemokine and ECM greatly increase and, especially, large numbers of osteopontin mRNA are expressed in early EAM. Less

(1)心肌标志物初诊时sFas和sFasL水平升高是预测急性心肌炎预后的良好血清学指标。MCP-1可能在人急性心肌炎的发病机制和大鼠实验性自身免疫性心肌炎（EAM）的进展中发挥重要作用。血清IL-10水平可能在评价心脏结节病患者疾病活动性方面发挥作用。(2)心肌的治疗低剂量卡维地洛对实验性自身免疫性心肌炎慢性期心肌纤维化面积明显减少。比索洛尔通过减少EAM患者的猝死而独立改善左心室功能。(3) EAM基因治疗是一种在体内通过电穿孔将基因转移到肌肉中治疗自身免疫性心肌炎的更有效的方法，可以递送IL-10、INFγ受体igg、分泌白细胞蛋白酶抑制剂igg和CTLA4-IgG。(4)第14天eam α-心肌肌球蛋白基因表达量减少26倍，β-心肌肌球蛋白基因表达量增加3.9倍。第21天和第14天，ANP和BNP分别增加48倍和6.4倍。AT1受体、ACE和ET1分别在第21天、21天和14天增加22倍、6.3倍和17倍。醛固酮受体在第14天下降2.2倍，醛固酮合成酶仅在第14天和第21天检测到。白细胞介素(IL) -2、IL-10、干扰素-γ和单核细胞趋化蛋白-1在第14天分别增加了9.1倍、398倍、43倍和142倍。第21天，3型胶原蛋白、1型胶原蛋白和纤维连接蛋白分别增加35倍、1.7倍和45倍。有趣的是，骨桥蛋白在第14天增加了4542倍，是所有mRNA中最高的。心肌肌球蛋白和NP的异构体在EAM中发生了显著变化。RAA和ET的表达在EAM时间过程中有不同的变化。细胞因子、趋化因子和ECM显著增加，尤其是骨桥蛋白mRNA在EAM早期大量表达。少

项目成果

Fuse, K.: "Enhanced expression and production of monocyte chemoattractant protein 1 in myocarditis"Clin Exp Immunol. 124. 346-352 (2001)

Fuse, K.：“心肌炎中单核细胞趋化蛋白 1 的表达和产生增强”Clin Exp Immunol。

Watanabe, K.: "Acute effects of endotheiin-1 and TAK-044 (ET(A) and ET(B) receptor antagonist) in rats with dilated cardiomyopathy"J Cardiovasc Pharmacol. 36. S49-54 (2000)

Watanabe, K.：“内皮素-1 和 TAK-044（ET(A) 和 ET(B) 受体拮抗剂）对扩张型心肌病大鼠的急性作用”J Cardiovasc Pharmacol。

Watanabe Kら: "Bisoprolol improves survival in rats with heart failure"J Cardiovasc Pharmacol. 38. S55-S58 (2001)

Watanabe K 等人：“比索洛尔改善心力衰竭大鼠的存活率”J Cardiovasc Pharmacol 38. S55-S58 (2001)

Ohta, Y.: "Carvedilol enhances atrial and brain natriuretic peptide mRNA expression and release in rat heart"J Cardiovasc Pharmacol. 36. S19-23 (2000)

Ohta, Y.：“卡维地洛增强大鼠心脏中心房和脑钠尿肽 mRNA 的表达和释放”J Cardiovasc Pharmacol。

Watanabe, K.: "Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy"Br J Pharmacol. 130. 1489-95 (2000)

Watanabe, K.：“低剂量卡维地洛抑制扩张型心肌病大鼠心力衰竭的进展”Br J Pharmacol。