Mao Weike, Fukuoka Shuji, Iwai Chikao, Liu Jiahao, Sharma Virendra K, Sheu Shey-Shing, Fu Michael, Liang Chang-seng
University of Rochester Medical Center, Department of Medicine, Cardiology Division, Box 679, 601 Elmwood Ave., Rochester, NY 14642, USA.
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1636-45. doi: 10.1152/ajpheart.01377.2006. Epub 2007 Jun 1.
Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the beta(1)-adrenergic receptor (beta(1)-EC(II)) is mediated via a biologically active anti-beta(1)-EC(II) antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the beta(1)-EC(II) autoantibody is a partial beta(1)-agonist, we speculate that the cardiomyopathy is produced by the beta(1)-receptor-mediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive beta(1)-EC(II) immunization, sham immunization, NE pellet, or beta(1)-EC(II) immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferase-mediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. beta(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the beta(1)-EC(II) antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by beta(1)-EC(II) peptide, and this is enhanced by increased NE and caused by activation of the beta(1)-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.
有证据表明，由与β₁ - 肾上腺素能受体第二细胞外环序列（β₁ - EC(II)）相对应的肽段所产生的自身免疫性心肌病是通过一种具有生物活性的抗β₁ - EC(II)抗体介导的，但该抗体与心肌细胞凋亡及心脏功能障碍之间的联系机制尚未完全阐明。由于β₁ - EC(II)自身抗体是一种部分β₁ - 激动剂，我们推测心肌病是由β₁ - 受体介导的CaMKII - p38 MAPK - ATF6信号通路激活和内质网（ER）应激所致，且过量的去甲肾上腺素（NE）会使心肌病加重。将兔子随机分为四组，分别接受β₁ - EC(II)免疫、假免疫、NE植入或β₁ - EC(II)免疫加NE植入，持续6个月。通过超声心动图和导管插入术测量心脏功能。通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和半胱天冬酶 - 3活性测定心肌细胞凋亡，而通过蛋白质印迹法、免疫组织化学和激酶活性测定法检测CaMKII、丝裂原活化蛋白激酶家族（JNK、p38、ERK）和内质网应激信号（ATF6、GRP78、CHOP、半胱天冬酶 - 12）。β₁ - EC(II)免疫可导致左心室逐渐扩张、收缩功能障碍和心肌细胞凋亡。这些变化与GRP78和CHOP的激活、半胱天冬酶 - 12切割增加以及CaMKII活性增加、p38 MAPK磷酸化增加和切割后的ATF6核转位有关。NE植入产生累加效应。此外，KN - 93和SB 203580可消除β₁ - EC(II)抗体在培养的新生心肌细胞中诱导的内质网应激和细胞凋亡。因此，内质网应激发生在由β₁ - EC(II)肽诱导的自身免疫性心肌病中，并且这种应激会因NE增加而增强，是由β₁ - 肾上腺素能受体偶联的CaMKII、p38 MAPK和ATF6信号通路激活所引起的。
