Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction
Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction
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DOI：
10.1038/labinvest.2008.85
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发表时间：
2008-11-01
影响因子：
5
通讯作者：
Chao, Julie
中科院分区：
文献类型：
--
作者：
Gao, Lin;Yin, Hang;Chao, Julie
氧化应激导致心肌细胞死亡和随后的心室功能障碍和心肌梗死（MI）后的心脏重塑，从而导致慢性心力衰竭患者的高死亡率。我们研究了在慢性心肌梗死大鼠模型和原代心肌细胞中激肽释放酶抑制剂在心脏重构中的作用。在结扎左冠状动脉后20分钟，心肌内注射人激肽释放酶抑制剂基因。在MI后4周，通过逆转录-聚合酶链反应、免疫组织化学和ELISA检测大鼠心脏中人激肽的表达。给药后可改善心功能，增加平均动脉压，缩小心肌梗死面积，恢复左室壁厚度。激肽释放酶抑制剂治疗显著减弱心肌细胞大小和心房钠尿肽表达。激肽释放酶抑制剂也减少胶原蛋白的积累，胶原蛋白分数的体积和表达的胶原蛋白I型和III型，转化生长因子β 1（TGF-β 1）和纤溶酶原激活物β 1在心肌。激肽抑制心肌肥厚和纤维化与增加心脏一氧化氮（NO）水平和减少超氧化物形成，NADH氧化酶活性和p22-phox表达。此外，在原代培养的大鼠心肌细胞和肌成纤维细胞中，重组Kallistatin抑制H2 O2诱导的细胞内超氧阴离子的形成，并且Kallistatin的抗氧化作用被N ω-硝基-L-精氨酸甲酯（L-NAME）消除，表明NO介导的事件。Kallistatin促进H2 O2处理的心肌细胞的存活，并抑制H2 O2诱导的Akt和ERK磷酸化以及NF-κ B B活化。此外，在培养的肌成纤维细胞中，激肽释放酶抑制剂消除了TGF-β诱导的胶原蛋白合成和分泌。这是第一项证明激肽通过其抗氧化作用改善心脏功能并预防MI后诱导的心脏肥大和纤维化的研究。
Oxidative stress causes cardiomyocyte death and subsequent ventricular dysfunction and cardiac remodeling after myocardial infarction (MI), thus contributing to high mortality in chronic heart failure patients. We investigated the effects of kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human kallistatin gene was injected intramyocardially 20 min after ligation of the left coronary artery. At 4 weeks after MI, expression of human kallistatin in rat hearts was identified by reverse transcription -polymerase chain reaction, immunohistochemistry and ELISA. Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased myocardial infarct size and restored left ventricular wall thickness. Kallistatin treatment significantly attenuated cardiomyocyte size and atrial natriuretic peptide expression. Kallistatin also reduced collagen accumulation, collagen fraction volume and expression of collagen types I and III, transforming growth factor-beta 1 (TGF-beta 1) and plasminogen activator inhibitor-beta 1 in the myocardium. Inhibition of cardiac hypertrophy and fibrosis by kallistatin was associated with increased cardiac nitric oxide (NO) levels and decreased superoxide formation, NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant kallistatin inhibited intracellular superoxide formation induced by H2O2, and the antioxidant effect of kallistatin was abolished by N omega-nitro-L-arginine methyl ester (L-NAME), indicating a NO-mediated event. Kallistatin promoted survival of cardiomyocytes subjected to H2O2 treatment, and inhibited H2O2-induced Akt and ERK phosphorylation, as well as NF-kappa B activation. Furthermore, kallistatin abrogated TGF-beta-induced collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that kallistatin improves cardiac performance and prevents post-MI-induced cardiac hypertrophy and fibrosis through its antioxidant action.