Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor
Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor
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DOI：
10.1016/j.jacc.2006.02.072
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发表时间：
2006-08-01
影响因子：
24
通讯作者：
Marber, Michael S.
中科院分区：
文献类型：
--
作者：
Bellahcene, Mohamed;Jacquet, Sebastien;Marber, Michael S.
本研究的目的是确定p38丝裂原活化蛋白激酶（p38-MAPK）是否有助于肿瘤坏死因子-α（TNF α）诱导的收缩性depression.Background肿瘤坏死因子具有可能由不同下游途径的激活引起的有益和有害后果。肿瘤坏死因子激活p38-MAPK，一种与收缩抑制和心脏损伤有关的应激反应激酶。我们测量了存在和不存在10 ng/L时的左心室发展压（LVDP）以及舒张末容积与LVDP之间的关系结果在恒压下15 min内，TNF α显著降低远交系小鼠和mkk 3（+/+）小鼠的LVDP和冠脉流量。这种早期负性肌力作用与p38-MAPK及其间接底物HSP 27的显著磷酸化有关。在缺乏MKK 3的心脏中，TNF α不能激活p38-MAPK或引起显著的收缩功能障碍。在MAPK活化蛋白激酶2（MK2）缺陷心脏中，TNF α的作用同样减弱，心肌p38-MAPK蛋白含量显著降低，p38-MAPK催化位点抑制剂SB 203580（1 μ mol/l）也可减弱TNF α的作用。在恒定冠状动脉流量的条件下，TNF α诱导的p38-MAPK激活和收缩抑制虽然减弱，但对MKK 3的缺乏或SB 203580的存在仍然敏感。p38-MAPK在TNF α诱导的心肌细胞收缩抑制中的作用在SB 203580或缺乏MKK 3的小鼠心肌细胞中得到证实。结论肿瘤坏死因子通过MKK 3激活完整心脏和分离心肌细胞中的p38-MAPK。这种激活可能有助于TNF α的早期心脏抑制作用。
OBJECTIVES The purpose of this study was to determine whether p38 mitogen-activated protein kinase (p38-MAPK) contributes to tumor necrosis factor-alpha (TNF alpha)-induced contractile depression.BACKGROUND Tumor necrosis factor has both beneficial and detrimental consequences that may result from the activation of different downstream pathways. Tumor necrosis factor activates p38-MAPK, a stress-responsive kinase implicated in contractile depression and cardiac injury.METHODS In isolated hearts from mice lacking the p38-MAPK activator, MAPK kinase 3 (MKK3), perfused at constant coronary pressure or flow, we measured the left ventricular developed pressure (LVDP) and the relationship between end-diastolic volume and LVDP in the presence and absence of 10 ng/ml TNF alpha.RESULTS Within 15 min at constant pressure, TNF alpha significantly reduced LVDP and coronary flow in outbred and mkk3(+/+) mice. This early negative inotropic effect was associated with a marked phosphorylation of both p38-MAPK and its indirect substrate, HSP27. In hearts lacking MKK3, TNF alpha failed to activate p38-MAPK or to cause significant contractile dysfunction. The actions of TNF alpha were similarly attenuated in MAPK-activated protein kinase 2 (MK2)-deficient hearts, which have a marked reduction in myocardial p38-MAPK protein content, and by the p38-MAPK catalytic site inhibitor SB203580 (1 mu mol/l). Under conditions of constant coronary flow, the p38-MAPK activation and contractile depression induced by TNF alpha, though attenuated, remained sensitive to the absence of MKK3 or the presence of SB203580. The role of p38-MAPK in TNF alpha-induced contractile depression was confirmed in isolated murine cardiac myocytes exposed to SB203580 or lacking MKK3.CONCLUSIONS Tumor necrosis factor activates p38-MAPK in the intact heart and in isolated cardiac myocytes through MKK3. This activation likely contributes to the early cardiodepressant action of TNF alpha.