Endostatin is protective against monocrotaline-induced right heart disease through the inhibition of T-type Ca2+ channel
Endostatin is protective against monocrotaline-induced right heart disease through the inhibition of T-type Ca2+ channel
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DOI：
10.1007/s00424-016-1810-0
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发表时间：
2016-07-01
影响因子：
4.5
通讯作者：
Yamawaki, Hideyuki
中科院分区：
文献类型：
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作者：
Imoto, Keisuke;Kumatani, Sayaka;Yamawaki, Hideyuki
内皮抑素（ES）是胶原XVIII α 1的C-末端片段，具有有效的抗血管生成作用。ES通过抑制T型Ca~（2+）通道抑制肿瘤细胞增殖。T型钙通道在包括野百合碱（MCT）诱导的右心衰竭在内的心脏疾病中重新表达。本研究旨在阐明ES对MCT诱导的右心室疾病的T型钙通道的影响及其发病机制。给大鼠腹腔注射MCT或生理盐水。从右心室分离心肌细胞后，用膜片钳法测定T型钙通道电流（I（CaT））。在MCT注射后1周通过右颈静脉给予ES小干扰RNA（siRNA）或对照siRNA（20 μ g）1周后，进行超声心动图和组织学分析。MCT组大鼠RV I（CaT）明显升高，ES组明显抑制I（CaT），而ES siRNA组大鼠存活率明显降低。在超声心动图中，尽管ES siRNA不影响肺动脉压，但与对照siRNA给药MCT大鼠（MCT Escsi组）相比，MCT ES si组的RV收缩功能受损。在RV组织学分析中，MCT组ES表达增加，ES siRNA抑制ES表达。此外，尽管MCT组仅显示心肌细胞肥大，但MCT ES组显示细胞间隙显著扩大。本研究首次揭示了ES抑制MCT注射大鼠RV的T型Ca~（2+）通道活性。ES基因敲低可加重MCT诱导的右心疾病ES可能通过抑制T-型Ca~（2+）通道活性发挥心脏保护作用。
Endostatin (ES), a C-terminal fragment of collagen XVIII alpha 1, has a potent anti-angiogenic effect. ES prevents tumor proliferation through inhibiting T-type Ca2+ channel. T-type Ca2+ channel is re-expressed during heart diseases including monocrotaline (MCT)-induced right heart failure. The present study aimed to clarify the effects of ES on T-type Ca2+ channel and pathogenesis of MCT-induced right ventricular disease. MCT or saline was injected intraperitoneally to rats. After cardiomyocytes were isolated from right ventricles (RVs), T-type Ca2+ channel current (I (CaT)) was measured by a patch-clamp method. After ES small interfering RNA (siRNA) or control siRNA (20 mu g) was administrated for 1 week via the right jugular vein 1 week after MCT injection, echocardiography and histological analysis were done. I (CaT) was significantly increased in RV from MCT-injected rats, and ES significantly inhibited it. The survival rate of ES siRNA-administrated MCT rats (MCT ES si group) was decreased. In echocardiography, although ES siRNA did not affect pulmonary arterial pressure, RV systolic function was impaired in MCT ES si group compared with control siRNA-administrated MCT rats (MCT cont si group). In the histological analysis of RV, ES expression was increased in MCT cont si group, and ES siRNA inhibited it. Furthermore, although MCT cont si group showed only cardiomyocyte hypertrophy, MCT ES si group showed notable enlargement of intercellular spaces. The present study for the first time revealed that ES inhibits T-type Ca2+ channel activity in RV from MCT-injected rats. ES gene knockdown deteriorates MCT-induced right heart disease. ES is thus cardioprotective possibly through inhibiting T-type Ca2+ channel activity.