Jane-wit Daniel, Altuntas Cengiz Z, Johnson Justin M, Yong Sandro, Wickley Peter J, Clark Pamela, Wang Qing, Popović Zoran B, Penn Marc S, Damron Derek S, Perez Dianne M, Tuohy Vincent K
Department of Immunology, NB30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA.
Circulation. 2007 Jul 24;116(4):399-410. doi: 10.1161/CIRCULATIONAHA.106.683193. Epub 2007 Jul 9.
Antibodies to the beta1-adrenergic receptor (beta1AR) are detected in a substantial number of patients with idiopathic dilated cardiomyopathy (DCM). The mechanism whereby these autoantibodies exert their pathogenic effect is unknown. Here, we define a causal mechanism whereby beta1AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM.
We used the beta1AR protein as an immunogen in SWXJ mice and generated a polyclonal battery of autoantibodies that showed selective binding to the beta1AR. After transfer into naive male hosts, beta1AR antibodies elicited fulminant DCM at high frequency. DCM was attenuated after immunoadsorption of beta1AR IgG before transfer and by selective pharmacological antagonism of host beta1AR but not beta2AR. We found that beta1AR autoantibodies shifted the beta1AR into the agonist-coupled high-affinity state and activated the canonical cAMP-dependent protein kinase A signaling pathway in cardiomyocytes. These events led to functional alterations in intracellular calcium handling and contractile function. Sustained agonism by beta1AR autoantibodies elicited caspase-3 activation, cardiomyocyte apoptosis, and DCM in vivo, and these processes were prevented by in vivo treatment with the pan-caspase inhibitor Z-VAD-FMK.
Our data show how beta1AR-specific autoantibodies elicit DCM by agonistically inducing cardiomyocyte apoptosis.
在大量特发性扩张型心肌病（DCM）患者中检测到β1肾上腺素能受体（β1AR）抗体。这些自身抗体发挥致病作用的机制尚不清楚。在此，我们确定了一种因果机制，即β1AR特异性自身抗体在小鼠DCM期间介导非炎性心肌细胞死亡。
我们将β1AR蛋白用作SWXJ小鼠的免疫原，并产生了一组多克隆自身抗体，这些抗体显示出对β1AR的选择性结合。将其转移到未接触过的雄性宿主后，β1AR抗体高频引发暴发性DCM。在转移前对β1AR IgG进行免疫吸附后，以及通过对宿主β1AR而非β2AR的选择性药理拮抗作用，DCM得到缓解。我们发现β1AR自身抗体将β1AR转变为激动剂偶联的高亲和力状态，并激活心肌细胞中的经典cAMP依赖性蛋白激酶A信号通路。这些事件导致细胞内钙处理和收缩功能的功能改变。β1AR自身抗体的持续激动作用在体内引发半胱天冬酶-3激活、心肌细胞凋亡和DCM，并且这些过程可通过用泛半胱天冬酶抑制剂Z-VAD-FMK进行体内治疗来预防。
我们的数据表明β1AR特异性自身抗体如何通过激动诱导心肌细胞凋亡引发DCM。
