Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy.
Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy.
复制标题
激肽释放酶相关肽酶 8 在心肌中表达并诱导心脏肥大
DOI：
10.1038/srep20024
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发表时间：
2016-01-29
影响因子：
4.6
通讯作者：
Ni X
中科院分区：
文献类型：
--
作者：
Cao B;Yu Q;Zhao W;Tang Z;Cong B;Du J;Lu J;Zhu X;Ni X
组织激肽释放酶相关多肽酶家族(KLK)是一组与亲本组织激肽释放酶(KLK1)有相似同源性的胰酶和糜蛋白酶样丝氨酸蛋白酶。KLK1在心脏中被发现，具有抗肥厚作用。然而，KLK家族的其他成员是否在心脏功能调节中发挥作用尚不清楚。在本研究中，我们首次证明了KLK8在心肌中表达。心肌肥厚模型大鼠左室心肌KLK8表达上调。心肌腺病毒介导的KLK8和转基因介导的KLK8过表达均可导致体内心脏肥大。在原代新生大鼠心肌细胞中，KLK8基因敲除抑制了苯肾上腺素(PE)诱导的心肌细胞肥大，而KLK8过表达则通过依赖丝氨酸蛋白酶活性但不依赖激动素受体的途径促进心肌细胞肥大。KLK8过表达增加了表皮生长因子(EGF)的产生，这一作用可被丝氨酸蛋白酶抑制剂阻断。表皮生长因子受体(EGFR)拮抗剂和EGFR基因敲除可逆转KLK8过度表达所致的肥大。阻断蛋白酶激活受体1(PAR1)或PAR2通路，KLK8诱导的心肌细胞肥大也明显减轻。我们的数据表明，KLK8可能通过EGF信号和PARs依赖但不依赖激动素受体的途径促进心肌细胞肥大。提示不同的KLK家族成员对心功能和重构具有微妙的调节作用。
The tissue kallikrein-related peptidase family (KLK) is a group of trypsin- and chymotrypsin-like serine proteases that share a similar homology to parent tissue kallikrein (KLK1). KLK1 is identified in heart and has anti-hypertrophic effects. However, whether other KLK family members play a role in regulating cardiac function remains unknown. In the present study, we demonstrated for the first time that KLK8 was expressed in myocardium. KLK8 expression was upregulated in left ventricle of cardiac hypertrophy models. Both intra-cardiac adenovirus-mediated and transgenic-mediated KLK8 overexpression led to cardiac hypertrophyin vivo. In primary neonatal rat cardiomyocytes, KLK8 knockdown inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas KLK8 overexpression promoted cardiomyocyte hypertrophy via a serine protease activity-dependent but kinin receptor-independent pathway. KLK8 overexpression increased epidermal growth factor (EGF) production, which was blocked by the inhibitors of serine protease. EGF receptor (EGFR) antagonist and EGFR knockdown reversed the hypertrophy induced by KLK8 overexpression. KLK8-induced cardiomyocyte hypertrophy was also significantly decreased by blocking the protease-activated receptor 1 (PAR1) or PAR2 pathway. Our data suggest that KLK8 may promote cardiomyocyte hypertrophy through EGF signaling- and PARs-dependent but a kinin receptor-independent pathway. It is implied that different KLK family members can subtly regulate cardiac function and remodeling.