Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction.
Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction.
复制标题
自身蛋白毒素抑制可减少心脏炎症，并减轻心肌梗塞后心脏重塑。
DOI：
10.1016/j.yjmcc.2020.09.011
复制
发表时间：
2020-12
影响因子：
5
通讯作者：
Abdel-Latif A
中科院分区：
文献类型：
--
作者：
Tripathi H;Al-Darraji A;Abo-Aly M;Peng H;Shokri E;Chelvarajan L;R Donahue R;Levitan BM;Gao E;Hernandez G;Morris AJ;Smyth SS;Abdel-Latif A
急性心肌梗死(AMI)会引发病理性炎症，从而加重组织损伤，导致心力衰竭。溶血磷脂酸(LPA)由自体趋化蛋白(ATX)产生，促进炎症和动脉粥样硬化的发展。ATX/LPA信号通路在心脏炎症和由此导致的不良心脏重塑中的作用尚不清楚。我们评估了急性心肌梗死患者和C57BL/6(WT)小鼠的自体趋化蛋白活性和LPA水平与心脏和全身炎症的关系。人和小鼠外周血和心脏组织样本显示，急性心肌梗死后ATX活性、LPA和炎症细胞水平升高，LPA水平与循环炎症细胞密切相关。在获得功能模型中，脂磷酸酶3(LPP3)特异性诱导基因敲除(Mx1-Plpp3Δ)显示急性心肌梗死后的全身和心脏炎症反应比同年龄对照组(Mx1-Plpp3f1/f1)更高，骨髓祖细胞计数和增殖也相应增加。此外，在Mx1-plpp3Δ小鼠中，心功能恢复减少，心脏不良重塑和疤痕大小相应增加(通过超声心动图和马森三色染色进行评估)。为了观察ATX/LPA联结抑制的效果，我们用特殊的药物抑制剂PF8380治疗急性心肌梗死后的WT小鼠，每天两次，连续7天。抑制ATX/LPA信号通路可显著降低急性心肌梗死后的炎症反应，使心功能恢复良好，减少瘢痕面积，促进血管生成。ATX/LPA信号通路在急性心肌梗死后炎症反应的调节中起重要作用，针对该机制的研究为急性心肌损伤患者提供了一种新的治疗靶点。自体趋化蛋白/溶血磷脂酸信号在急性心肌梗死后炎症和心功能不全中的作用示意图。死亡的心肌细胞和心脏成纤维细胞释放的损伤相关的分子模式分子启动炎症级联反应，导致自体趋化蛋白/溶血磷脂酸信号的激活，进而通过释放炎症细胞因子和趋化因子而加剧局部和全身炎症。全身而言，骨髓祖细胞的激活会导致炎性细胞的产生增加。局部，如MCP-1等化学诱导剂的增加会导致炎症细胞对受损心肌的渗透增加。总体而言，这些事件会导致炎症反应延长和加剧，并损害心脏功能的恢复。
Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson’s Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury. Schematic summarizing the role of autotaxin/lysophosphatidic acid signaling in post-AMI inflammation and cardiac dysfunction. Damage associated molecular pattern molecules released from dying cardiomyocytes and cardiac fibroblasts initiate an inflammatory cascade resulting in the activation of Autotaxin/Lysophosphatidic acid signaling; which in turn augments local and systemic inflammation through the release of inflammatory cytokines and chemokines. Systemically, activation of bone marrow progenitors results in increased production of inflammatory cells. Locally, increased chemoattractants such as MCP-1 results in increased infiltration of inflammatory cells to the damaged myocardium. Collectively, these events result in prolonged and exacerbated inflammatory response and impaired cardiac functional recovery.
登录
查看更多内容
影响因子：
3.7
作者：
Annamalai L;Westmoreland SV;Domingues HG;Walsh DG;Gonzalez RG;O'Neil SP
通讯作者：
O'Neil SP
影响因子：
29
作者：
Nagareddy PR;Kraakman M;Masters SL;Stirzaker RA;Gorman DJ;Grant RW;Dragoljevic D;Hong ES;Abdel-Latif A;Smyth SS;Choi SH;Korner J;Bornfeldt KE;Fisher EA;Dixit VD;Tall AR;Goldberg IJ;Murphy AJ
通讯作者：
Murphy AJ
影响因子：
37.8
作者：
Bouchareb, Rihab;Mahmut, Ablajan;Mathieu, Patrick
通讯作者：
Mathieu, Patrick
影响因子：
5.9
作者：
BULKLEY, BH;ROBERTS, WC
通讯作者：
ROBERTS, WC
DOI：
10.1080/00365510310003265
发表时间：
2003-01-01
影响因子：
2.1
作者：
Chen, X;Yang, XY;Chen, JH
通讯作者：
Chen, JH