Department of Cardiology, University Medical Center, Utrecht, The Netherlands.
Circ Heart Fail. 2013 Jul;6(4):853-61. doi: 10.1161/CIRCHEARTFAILURE.112.000255. Epub 2013 May 2.
Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail.
Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15; P<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6; P=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells.
High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.
更好地了解重构的分子机制已成为心力衰竭（HF）研究的主要目标，以阻止或逆转其进展。左心室辅助装置（LVAD）正被用于 HF 患者，导致部分反向重构。在本研究中，蛋白质组学在 LVAD 支持期间鉴定了α-1-抗胰蛋白酶（ACT）水平的显著变化。此外，还详细研究了 ACT 在反向重构中的潜在作用。
与 LVAD 前组织相比，LVAD 后心肌组织中 ACT mRNA 的表达（定量聚合酶链反应）显著降低（n=15；P<0.01）。免疫组织化学显示，ACT 的表达和定位在 LVAD 支持期间发生了变化。HF 患者的循环 ACT 水平升高（n=18），与健康对照组（n=6；P=0.001）相比，LVAD 支持 6 个月后恢复正常。由于越来越多的证据表明 microRNAs（miRs）参与心肌疾病过程，我们还研究了 ACT 是否受 miR 转录后调控。生物信息学分析指出 miR-137 可能是 ACT 的调节因子。miR-137 在心肌组织中的表达与 ACT mRNA 呈负相关。荧光素酶活性测定证实 ACT 是 miR-137 的直接靶标，原位杂交表明 ACT 和 miR-137 主要定位于心肌细胞和基质细胞。
HF 患者的高 ACT 血浆水平在 LVAD 支持期间恢复正常，这与心脏组织中 ACT mRNA 的减少一致，而 miR-137 水平增加。miR-137 直接靶向 ACT，表明 ACT 和 miR-137 在 HF 的病理生理学和机械支持期间的反向重构中发挥作用。
