Legumain is a predictor of all-cause mortality and potential therapeutic target in acute myocardial infarction.
Legumain is a predictor of all-cause mortality and potential therapeutic target in acute myocardial infarction.
复制标题
Legumain 是全因死亡率的预测因子和急性心肌梗死的潜在治疗靶点
DOI：
10.1038/s41419-020-03211-4
复制
发表时间：
2020-11-26
影响因子：
9
通讯作者：
Zhou S
中科院分区：
文献类型：
--
作者：
Yang H;He Y;Zou P;Hu Y;Li X;Tang L;Zhu Z;Tai S;Tu T;Xiao Y;Chen M;Wu C;Zhou S
急性心肌梗死（AMI）后细胞外基质（ECM）调节及其调节机制的预后影响需要进一步澄清。在此，我们探讨了豆类蛋白的预测作用，它显示了ECM降解的能力，在AMI患者队列和调查的潜在机制。共有212名AMI患者和323名健康对照者参加了这项研究。采用永久性结扎左前降支的方法建立小鼠急性心肌梗死模型，并采用成纤维细胞进行机制分析。根据受试者工作特征曲线的截止值，将AMI患者分为低（n = 168）和高（n = 44）血浆豆荚蛋白浓度（PLG）组。AMI组PLG水平中位数为5.9 μg/L（四分位距：4.2-9.3 μg/L），明显高于健康对照组（中位数4.4 μg/L（四分位距：3.2-6.1 μg/L），P < 0.001）。高PLG组的全因死亡率显著高于低PLG组（中位随访期为39.2个月; 31.8% vs. 12.5%; P = 0.002）。多变量考克斯回归分析显示，调整临床混杂因素后，高PLG与全因死亡率增加相关（HR = 3.1，95%置信区间（CI）= 1.4-7.0，P = 0.005）。与临床观察结果一致，实验性AMI小鼠外周血和梗死心脏组织中的legumain浓度也增加。用RR-11 a阻断legumain，改善心功能，降低心脏破裂率，并减弱AMI后左室扩张和室壁变薄。因此，血浆legumain浓度在AMI患者中具有预后价值。此外，豆荚蛋白通过促进ECM降解来抑制心脏重塑，ECM降解至少部分地通过MMP-2途径的活化而发生。
The prognostic impact of extracellular matrix (ECM) modulation and its regulatory mechanism post-acute myocardial infarction (AMI), require further clarification. Herein, we explore the predictive role of legumain—which showed the ability in ECM degradation—in an AMI patient cohort and investigate the underlying mechanisms. A total of 212 AMI patients and 323 healthy controls were enrolled in the study. Moreover, AMI was induced in mice by permanent ligation of the left anterior descending artery and fibroblasts were adopted for mechanism analysis. Based on the cut-off value for the receiver-operating characteristics curve, AMI patients were stratified into low (n = 168) and high (n = 44) plasma legumain concentration (PLG) groups. However, PLG was significantly higher in AMI patients than that in the healthy controls (median 5.9 μg/L [interquartile range: 4.2–9.3 μg/L] vs. median 4.4 μg/L [interquartile range: 3.2–6.1 μg/L], P < 0.001). All-cause mortality was significantly higher in the high PLG group compared to that in the low PLG group (median follow-up period, 39.2 months; 31.8% vs. 12.5%; P = 0.002). Multivariate Cox regression analysis showed that high PLG was associated with increased all-cause mortality after adjusting for clinical confounders (HR = 3.1, 95% confidence interval (CI) = 1.4–7.0, P = 0.005). In accordance with the clinical observations, legumain concentration was also increased in peripheral blood, and infarcted cardiac tissue from experimental AMI mice. Pharmacological blockade of legumain with RR-11a, improved cardiac function, decreased cardiac rupture rate, and attenuated left chamber dilation and wall thinning post-AMI. Hence, plasma legumain concentration is of prognostic value in AMI patients. Moreover, legumain aggravates cardiac remodelling through promoting ECM degradation which occurs, at least partially, via activation of the MMP-2 pathway.
登录
查看更多内容
影响因子：
20.1
作者：
Gao E;Lei YH;Shang X;Huang ZM;Zuo L;Boucher M;Fan Q;Chuprun JK;Ma XL;Koch WJ
通讯作者：
Koch WJ
影响因子：
4.6
作者：
Lei, Qian;Yi, Tao;Wang, Yanggan
通讯作者：
Wang, Yanggan
影响因子：
19.7
作者：
HANLEY, JA;MCNEIL, BJ
通讯作者：
MCNEIL, BJ
影响因子：
37.8
作者：
Iraqi, Wafae;Rossignol, Patrick;Zannad, Faiez
通讯作者：
Zannad, Faiez
影响因子：
1.9
作者：
DELONG, ER;DELONG, DM;CLARKEPEARSON, DI
通讯作者：
CLARKEPEARSON, DI