L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices
L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices
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DOI：
10.1161/01.res.0000033988.13062.7c
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发表时间：
2002-09-20
影响因子：
20.1
通讯作者：
Houser, SR
中科院分区：
文献类型：
--
作者：
Chen, XW;Piancentino, V;Houser, SR
Ca2+ 通过 L 型钙通道 (LTCC) 流入，诱导肌浆网 (SR) 释放 Ca2+，并维持 SR Ca2+ 负荷。研究了 LTCC 特性的改变、它们对衰竭心脏中肾上腺素能反应性减弱的影响以及左心室辅助装置 (LVAD) 支持后的恢复。在基础条件下，在异丙肾上腺素 (ISO)、二丁酰-cAMP (db-cAMP)、Bay K 8644 (BayK)、冈田酸（OA，磷酸酶抑制剂）和磷酸酶 2A (MA) 存在的情况下，测量非衰竭 (NF)、衰竭 (F) 和 LVAD 支持的人左心室肌细胞中的 L 型 Ca2+ 电流 (I-Ca,I-L) （HVM）。 3 组中的基础 I-Ca,I-L 密度没有差异，但与 NF-HVM 相比，F- 和 LVAD- 中 I-Ca,I-L 在更负的电压下被激活（V-0 5：-7.18+/-1.4 和 -7.0 +/- 0.9 与 0.46 +/- 1.1 mV）。 ISO 和 db-cAMP 均比 F-HVM 中的 NF- 和 LVAD- 显着增加 I-Ca,I-L（NF >LVAD> F：ISO：90 +/- 15% 对比 77 +/- 19% 对比 24 +/- 12%；db-cAMP：235%>172%>90%）。 ISO 导致 NF- 和 LVAD- 中 I-Ca、I-L 激活曲线显着左移，但在 F-HVM 中则不然。 ISO 和 db-cAMP 后，I-Ca、I-L 激活在组间没有显着差异。 BayK 还使 NF-(81 +/- 30%) 和 LVAD-(70 +/- 15%) 中的 I-Ca,I-L 比 F-(51 +/- 8%) HVM 中增加更多。 OA 使 NF-HVM 中的 I-Ca,I-L 增加 85.6%，但对 F-HVM 没有影响，而 PP2A 使 F-HVM 中的 I-Ca,I-L 降低 35%，但对 NF-HVM 没有影响。这些结果表明，F-HVM 中 LTCC 的密度降低，但基础 I-Ca、I-L 密度通过增加 LTCC 磷酸化而得以维持。
Ca2+ influx through the L-type calcium channel (LTCC) induces Ca2+ release from the sarcoplasmic reticulum (SR) and maintains SR Ca2+ loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca2+ current (I-Ca,I-L) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (MA) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal I-Ca,I-L density was not different in the 3 groups but I-Ca,I-L was activated at more negative voltages in F- and LVAD- versus NF-HVMs (V-0 5: -7.18+/-1.4 and -7.0 +/- 0.9 versus 0.46 +/- 1.1 mV). Both ISO and db-cAMP increased I-Ca,I-L in NF- and LVAD- significantly more than in F-HVMs (NF >LVAD> F: ISO: 90 +/- 15% versus 77 +/- 19% versus 24 +/- 12%; db-cAMP: 235%>172%>90%). ISO caused a significant leftward shift of the I-Ca,I-L activation curve in NF- and LVAD- but not in F-HVMs. After ISO and db-cAMP, the I-Ca,I-L activation was not significantly different between groups. BayK also increased I-Ca,I-L more in NF-(81 +/- 30%) and LVAD- (70 +/- 15 %) than in F- (51 +/- 8%) HVMs. OA increased I-Ca,I-L by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased I-Ca,I-L in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal I-Ca,I-L density is maintained by increasing in LTCC phosphorylation.