Rescue and Worsening of Congenital Heart Block-Associated Electrocardiographic Abnormalities in Two Transgenic Mice
Rescue and Worsening of Congenital Heart Block-Associated Electrocardiographic Abnormalities in Two Transgenic Mice
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DOI：
10.1111/j.1540-8167.2011.02032.x
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发表时间：
2011-08-01
影响因子：
2.7
通讯作者：
Boutjdir, Mohamed
中科院分区：
文献类型：
--
作者：
Karnabi, Eddy;Qu, Yongxia;Boutjdir, Mohamed
CHB转基因小鼠模型。先天性心脏传导阻滞（CHB）是一种被动获得性自身免疫性疾病，被认为是由于母体自身抗体（抗ssa /Ro -SSB/La）向胎儿转移导致房室传导阻滞和窦性心动过缓。我们之前建立了一个CHB小鼠模型，其中免疫野生型（WT）母鼠所生的幼鼠表现出与CHB相似的心电图异常，并表现出l型Ca通道（ltcc）被母体抗体抑制。在这里，我们假设LTCC的过表达可以挽救，而LTCC的敲除会加重小鼠的心电图异常。方法与结果：用SSA/Ro和SSB/La抗原免疫转基因小鼠。与未免疫WT母鼠所生的幼崽相比，免疫WT母鼠所生的幼崽有明显更大的窦性心动过缓和房室传导阻滞。与未免疫WT母鼠和免疫WT母鼠所生的幼崽相比，过表达LTCC的TG幼崽有明显更少的窦性心动过缓和房室传导阻滞。接种疫苗的母亲所生的所有LTCC基因敲除幼崽均有窦性心动过缓、房室传导阻滞程度加重和胎次减少。未免疫WT母鼠的幼崽未出现窦性心动过缓或房室传导阻滞。CHB患儿母亲的IgG，而非正常IgG，完全抑制细胞内Ca瞬态（[Ca](i)T）振幅。结论：心脏特异性过表达LTCC可显著降低暴露于抗ssa /Ro -SSB/La自身抗体的幼犬房室传导阻滞和窦性心动过缓的发生率，而LTCC基因敲除的幼犬暴露于这些自身抗体显著加重了心电图异常。这些发现支持了母体抗体抑制LTCC和[Ca] iT从而促进CHB发展的假设。总之，这些结果与慢性乙型肝炎新疗法的发展有关。（journal cardiovascular Electrophysiol, Vol. 22, pp. 922-930, August 2011）
Transgenic Murine Models of CHB. Introduction: Congenital heart block (CHB) is a passively acquired autoimmune disease considered to be due to the transfer of maternal autoantibodies, anti-SSA/Ro -SSB/La, to the fetus resulting in atrioventricular (AV) block and sinus bradycardia. We previously established a murine model for CHB where pups born to immunized wild-type (WT) mothers exhibited electrocardiographic abnormalities similar to those seen in CHB and demonstrated inhibition of L-type Ca channels (LTCCs) by maternal antibodies. Here, we hypothesize that overexpression of LTCC should rescue, whereas knockout of LTCC should worsen the electrocardiographic abnormalities in mice.Methods and Results: Transgenic (TG) mice were immunized with SSA/Ro and SSB/La antigens. Pups born to immunized WT mothers had significantly greater sinus bradycardia and AV block compared to pups from nonimmunized WT. TG pups overexpressing LTCC had significantly less sinus bradycardia and AV block compared to their non-TG littermates and to pups born to immunized WT mothers. All LTCC knockout pups born to immunized mothers had sinus bradycardia, advanced degree of AV block, and decreased fetal parity. No sinus bradycardia or AV block were manifested in pups from control nonimmunized WT mothers. IgG from mothers with CHB children, but not normal IgG, completely inhibited intracellular Ca transient ([Ca](i)T) amplitude.Conclusions: Cardiac-specific overexpression of LTCC significantly reduced the incidence of AV block and sinus bradycardia in pups exposed to anti-SSA/Ro -SSB/La autoantibodies, whereas exposure of LTCC knockout pups to these autoantibodies significantly worsened the electrocardiographic abnormalities. These findings support the hypothesis that maternal antibodies inhibit LTCC and [Ca] iT thus contributing to the development of CHB. Altogether, the results are relevant to the development of novel therapies for CHB. (J Cardiovasc Electrophysiol, Vol. 22, pp. 922-930, August 2011)