Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies.
Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies.
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DOI：
10.1080/08916930802031579
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发表时间：
2008-09
期刊：
影响因子：
3.5
通讯作者：
Cunningham MW
中科院分区：
文献类型：
--
作者：
Mascaro-Blanco A;Alvarez K;Yu X;Lindenfeld J;Olansky L;Lyons T;Duvall D;Heuser JS;Gosmanova A;Rubenstein CJ;Cooper LT;Kem DC;Cunningham MW
心肌炎通常由病毒感染引起，可发展为自身免疫性炎症性心脏病、扩张型心肌病和心力衰竭。尽管心肌肌球蛋白是心肌炎动物模型中的显性自身抗原，并且在病毒性心肌炎期间从心脏释放，但抗心肌肌球蛋白自身抗体的特性、作用和意义尚不明确。在我们的研究中，我们定义了人心肌炎和心肌病中的人心肌肌球蛋白表位，并建立了一种机制来解释抗心肌肌球蛋白自身抗体如何促进心脏病。我们发现，心肌炎和扩张型心肌病患者血清中针对心肌肌球蛋白的自身抗体主要靶向心肌肌球蛋白S2铰链区的表位。此外，血清中的抗心肌肌球蛋白抗体或来自心肌炎和心肌病的纯化IgG靶向β -肾上腺素能受体，并诱导抗体介导的心脏细胞中camp依赖性蛋白激酶A （PKA）细胞信号传导活性。抗体介导的PKA活性在血清中被抗人IgG吸收。抗体介导的PKA细胞信号被人心肌蛋白或β -肾上腺素能受体的抗原特异性抑制所阻断，而α -肾上腺素能受体或牛血清白蛋白则不被阻断。普萘洛尔是一种β受体阻滞剂和β肾上腺素受体途径的抑制剂，也阻断了β肾上腺素受体和PKA的抗体介导的信号传导。这些数据表明，抗人心肌肌球蛋白的IgG抗体与β -肾上腺素能受体反应并触发心脏细胞中的PKA信号。总之，我们已经发现了一类新的针对人心肌肌球蛋白和心脏β -肾上腺素能受体的交叉反应性自身抗体。此外，我们已经确定了人类心肌炎和心肌病患者心肌肌球蛋白棒S2区域的疾病特异性肽表位，以及自身抗体在疾病发病机制中的机制作用。
Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In-summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.
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