Thum Thomas, Fraccarollo Daniela, Galuppo Paolo, Tsikas Dimitrios, Frantz Stefan, Ertl Georg, Bauersachs Johann
Medizinische Klinik I, Kardiologie, Universitätsklinikum Würzburg, Julius-Maximilians-Universität, Josef-Schneider Str. 2, 97080 Würzburg, Germany.
Cardiovasc Res. 2006 Apr 1;70(1):50-60. doi: 10.1016/j.cardiores.2006.01.002. Epub 2006 Feb 9.
Standard drugs post-myocardial infarction (MI) such as angiotensin converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) increase levels of endothelial progenitor cells (EPC). However, potential underlying mechanisms have not yet been investigated.
We studied the effects of ACE inhibition or statin treatment on EPC levels and on bone marrow molecular pathways involved in EPC mobilization after MI in rats. Three days post-infarction, acetylated LDL (acLDL)+/Ulex europeus-1 (UEA-1)+/VEGF receptor-2+/eNOS+ EPC levels and formation of endothelial colony forming units (CFU) were reduced to 60+/-12% (p < 0.05) and 68+/-7% (p < 0.05). In bone marrow, extracellular signal-regulated kinase (ERK) phosphorylation and matrix metalloproteinase (MMP)-9 activity were repressed. Endothelial nitric oxide synthase (eNOS) activity was unchanged, whereas reactive oxygen species (ROS) were increased two-fold in bone marrow. ACE or HMG-CoA reductase inhibition resulted in significant increases in EPC levels. ACE inhibition increased bone marrow ERK phosphorylation and MMP-9 activity. Statin therapy enhanced bone marrow VEGF protein levels, Akt phosphorylation, eNOS activity and normalized increased ROS levels. Augmented EPC levels in the early post-infarction phase by ACE inhibition or statin treatment were associated with improved cardiac function and increased capillary density in the peri-infarct area 7 days after MI. Moreover, increased EPC levels in response to ACE inhibition or statin treatment were sustained 10 weeks post-infarction.
Increased ROS and impaired MMP-9 activity in bone marrow likely contribute to reduced EPC mobilization in the early post-infarction phase. ACE inhibition or statin treatment increased EPC levels with distinct drug-specific effects on bone marrow molecular alterations.
心肌梗死（MI）后的标准药物，如血管紧张素转换酶（ACE）抑制剂和3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）可提高内皮祖细胞（EPC）水平。然而，其潜在的机制尚未得到研究。
我们研究了ACE抑制或他汀类药物治疗对大鼠心肌梗死后EPC水平以及参与EPC动员的骨髓分子途径的影响。梗死后三天，乙酰化低密度脂蛋白（acLDL）+/欧洲荆豆凝集素-1（UEA-1）+/血管内皮生长因子受体-2+/内皮型一氧化氮合酶（eNOS）+ EPC水平以及内皮集落形成单位（CFU）的形成分别降至60±12%（p<0.05）和68±7%（p<0.05）。在骨髓中，细胞外信号调节激酶（ERK）磷酸化和基质金属蛋白酶（MMP）-9活性受到抑制。内皮型一氧化氮合酶（eNOS）活性未改变，而骨髓中的活性氧（ROS）增加了两倍。ACE或HMG-CoA还原酶抑制导致EPC水平显著升高。ACE抑制增加了骨髓ERK磷酸化和MMP-9活性。他汀类药物治疗提高了骨髓血管内皮生长因子（VEGF）蛋白水平、Akt磷酸化、eNOS活性，并使升高的ROS水平恢复正常。心肌梗死后早期通过ACE抑制或他汀类药物治疗使EPC水平升高与心肌梗死后7天心脏功能改善和梗死周边区域毛细血管密度增加有关。此外，ACE抑制或他汀类药物治疗引起的EPC水平升高在心肌梗死后10周仍持续存在。
骨髓中ROS增加和MMP-9活性受损可能导致心肌梗死后早期EPC动员减少。ACE抑制或他汀类药物治疗可提高EPC水平，对骨髓分子改变具有明显的药物特异性作用。
