Blockade of NF-κB improves cardiac function and survival after myocardial infarction
Blockade of NF-κB improves cardiac function and survival after myocardial infarction
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DOI：
10.1152/ajpheart.01175.2005
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发表时间：
2006-09-01
影响因子：
4.8
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Kawano, Shunichi;Kubota, Toru;Sunagawa, Kenji
NF-κ B是调节炎症过程的关键转录因子。在本研究中，我们验证了阻断NF-κ B可改善心肌梗死（MI）后心脏重构和心力衰竭的假设。使用具有NF-κ B的p50亚基的靶向破坏的敲除小鼠（KO）来阻断NF-κ B的活化。通过结扎雄性KO和年龄匹配的野生型（WT）小鼠的左冠状动脉诱导MI。NF-κ B B在WT + MI小鼠的非梗死和梗死心肌中被激活，而在KO小鼠中该活性完全消失。NF-κ B B阻滞剂可显著减少MI后早期心室破裂，并通过改善充血性心力衰竭改善生存率。超声心动图和压力测量显示，与WT + MI小鼠相比，KO + MI小鼠的左心室缩短分数和左心室压力的最大上升速率显著增加，舒张末期压力显著降低。组织学分析表明，KO + MI小鼠的非梗死心肌中的肌细胞肥大以及间质纤维化受到显著抑制。阻断NF-κ B并不能改善梗死或非梗死心肌中促炎细胞因子的表达。相比之下，KO + MI小鼠中c-Jun NH 2-末端激酶的磷酸化几乎完全消除。目前的研究表明，靶向破坏NF-κ B B的p50亚基可以减少心室破裂，改善心肌梗死后的心脏功能和存活率。阻断NF-κ B B可能是减轻心肌梗死后心脏重构和心力衰竭的一种新的治疗策略。
NF-kappa B is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappa B ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappa B (KO) were used to block the activation of NF-kappa B. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappa B was activated in noninfarct as well as infarct myocardium in WT + MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappa B significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO + MI mice compared with WT + MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO + MI mice. Blockade of NF-kappa B did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO + MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappa B reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappa B might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.