Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice.
Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice.
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凝血酶介导的PAR1激活增强了阿霉素诱导的小鼠心脏损伤。
DOI：
10.1182/bloodadvances.2022008637
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发表时间：
2023-05-23
期刊：
影响因子：
7.5
通讯作者：
Antoniak, Silvio
中科院分区：
文献类型：
--
作者：
Grover, Steven P.;Bharathi, Vanthana;Posma, Jens J.;Griffin, John H.;Palumbo, Joseph S.;Mackman, Nigel;Antoniak, Silvio
心肌细胞和心脏成纤维细胞PAR1参与阿霉素所致的心脏损伤。在阿霉素治疗导致心脏损伤的过程中，R41处的PAR1裂解提供了病理Galphaq信号。化疗药物阿霉素对心脏有毒性，可能导致不可逆转的心力衰竭。阿霉素除了对心脏有毒性外，还能诱导凝血系统的激活。我们测定了凝血酶介导的蛋白水解酶激活受体1(PAR1)在阿霉素诱导的心脏损伤中的作用。阿霉素能显著提高小鼠血浆凝血酶原片段1+2、凝血酶-抗凝血酶复合体和细胞外小泡组织因子活性。与对照组相比，表达低水平组织因子的阿霉素治疗的小鼠，而不是凝血因子XII缺陷的小鼠，血浆凝血酶-抗凝血酶复合体降低。为了评价凝血酶介导的PAR1激活的作用，对凝血酶(Par1R41Q)或活化蛋白C(Par1R46Q)不敏感的转基因小鼠进行了阿霉素诱导的急性和慢性心脏损伤模型，并与Par1野生型(Par1+/+)和PAR1缺陷(Par1-/-)小鼠进行了比较。与Par1+/+对照组相比，Par1R41Q和Par1-/-小鼠，而不是Par1R46Q小鼠，在注射阿霉素后，心脏损伤标志物心肌肌钙蛋白I的减少、心脏功能的保护和心脏纤维化的减轻。此外，用小分子抑制剂Q94抑制PAR1下游的GαQ信号显著地保护了PAR1+/+小鼠的心功能，但与载体对照组相比，在急性心脏损伤模型下的PAR1R41Q小鼠中则不能。此外，与对照组相比，在心肌细胞或心脏成纤维细胞中缺失PAR1的小鼠显示出较少的心脏损伤。综上所述，这些数据表明凝血酶介导的PAR1激活在阿霉素诱导的心脏损伤中起作用。
Cardiomyocyte and cardiac fibroblast PAR1 contribute to doxorubicin-induced cardiac injury. PAR1 cleavage at R41 confers pathologic Galphaq signaling during doxorubicin treatment leading to cardiac injury. The chemotherapeutic drug doxorubicin is cardiotoxic and can cause irreversible heart failure. In addition to being cardiotoxic, doxorubicin also induces the activation of coagulation. We determined the effect of thrombin-mediated activation of protease-activated receptor 1 (PAR1) on doxorubicin-induced cardiac injury. Administration of doxorubicin to mice resulted in a significant increase in plasma prothrombin fragment 1+2, thrombin-antithrombin complexes, and extracellular vesicle tissue factor activity. Doxorubicin-treated mice expressing low levels of tissue factor, but not factor XII-deficient mice, had reduced plasma thrombin-antithrombin complexes compared to controls. To evaluate the role of thrombin-mediated activation of PAR1, transgenic mice insensitive to thrombin (Par1R41Q) or activated protein C (Par1R46Q) were subjected to acute and chronic models of doxorubicin-induced cardiac injury and compared with Par1 wild-type (Par1+/+) and PAR1 deficient (Par1-/-) mice. Par1R41Q and Par1-/- mice, but not Par1R46Q mice, demonstrated similar reductions in the cardiac injury marker cardiac troponin I, preserved cardiac function, and reduced cardiac fibrosis compared to Par1+/+ controls after administration of doxorubicin. Furthermore, inhibition of Gαq signaling downstream of PAR1 with the small molecule inhibitor Q94 significantly preserved cardiac function in Par1+/+ mice, but not in Par1R41Q mice subjected to the acute model of cardiac injury when compared to vehicle controls. In addition, mice with PAR1 deleted in either cardiomyocytes or cardiac fibroblasts demonstrated reduced cardiac injury compared to controls. Taken together, these data suggest that thrombin-mediated activation of PAR1 contributes to doxorubicin-induced cardiac injury.
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影响因子：
20.1
作者：
Gadi I;Fatima S;Elwakiel A;Nazir S;Mohanad Al-Dabet M;Rana R;Bock F;Manoharan J;Gupta D;Biemann R;Nieswandt B;Braun-Dullaeus R;Besler C;Scholz M;Geffers R;Griffin JH;Esmon CT;Kohli S;Isermann B;Shahzad K
通讯作者：
Shahzad K
影响因子：
5.4
作者：
Hall C;Gehmlich K;Denning C;Pavlovic D
通讯作者：
Pavlovic D
影响因子：
1.9
作者：
Antoniak S;Cardenas JC;Buczek LJ;Church FC;Mackman N;Pawlinski R
通讯作者：
Pawlinski R
DOI：
10.1152/ajpheart.00339.2017
发表时间：
2018-04-01
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
--
作者：
Lindsey ML;Kassiri Z;Virag JAI;de Castro Brás LE;Scherrer-Crosbie M
通讯作者：
Scherrer-Crosbie M
影响因子：
3.3
作者：
Deng, Xiaoling;Mercer, Paul F.;Chambers, Rachel C.
通讯作者：
Chambers, Rachel C.