Inflammatory Serine Proteases Play a Critical Role in the Early Pathogenesis of Diabetic Cardiomyopathy.
Inflammatory Serine Proteases Play a Critical Role in the Early Pathogenesis of Diabetic Cardiomyopathy.
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DOI：
10.33594/000000190
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Rafiq, Khadija
中科院分区：
文献类型：
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作者：
Kolpakov, Mikhail A;Sikder, Kunal;Rafiq, Khadija
背景/目的：糖尿病性心肌病（DCM）以结构和功能改变为特征，可导致心力衰竭。DCM的发病机制有几种已知的机制，然而，将炎症与DCM联系起来的分子机制尚不完全清楚。为了了解这一机制，我们研究了炎症丝氨酸蛋白酶（ISPs）在DCM发展过程中的作用。方法：在诱导1型糖尿病（T1DM）后4、8、16、20周，分别用链脲佐菌素（50 mg/kg）腹腔注射参与主要ISPs成熟的二肽基肽酶I （DPPI）缺失的8周龄小鼠和野生型（WT）对照小鼠。诱导糖尿病后进行超声心动图测量、血糖和血红蛋白A1c分析、免疫印迹、qPCR、酶活性测定和DPPI、isp和炎症标志物的免疫组织化学（IHC）分析。采用Serius Red染色和qPCR检测左心室心肌纤维化。TUNEL法和免疫印迹法检测细胞凋亡。结果：糖尿病WT小鼠DPPI表达随ISP激活而升高，DPPI主要通过浸润中性粒细胞在左心室大量积累。在糖尿病dppi敲除（DPPI-KO）小鼠中，与糖尿病WT小鼠相比，ISPs激活、心肌细胞凋亡、纤维化和心功能显著降低。此外，DPPI-KO小鼠显示糖尿病诱导的整体炎症状态降低，表现为促炎细胞因子如tnf - α， il -1 β和IL-6的产生减少。结论：本研究阐明了ISPs在增强导致T1DM DCM发病机制的免疫反应中的新作用。据我们所知，这是第一个报道DPPI表达和激活促进炎症，从而增强心肌细胞凋亡，并导致随后导致DCM的不良心脏重塑的研究。
BACKGROUND/AIMS: Diabetic cardiomyopathy (DCM) is characterized by structural and functional alterations that can lead to heart failure. Several mechanisms are known to be involved in the pathogenesis of DCM, however, the molecular mechanism that links inflammation to DCM is incompletely understood. To learn about this mechanism, we investigated the role of inflammatory serine proteases (ISPs) during the development of DCM.METHODS: Eight weeks old mice with deletion of dipeptidyl peptidase I (DPPI), an enzyme involved in the maturation of major ISPs, and wild type (WT) mice controls were injected with streptozotocin (50 mg/kg for 5 days intraperitoneally) and studied after 4, 8, 16, and 20 week after induction of type 1 diabetes mellitus (T1DM). Induction of diabetes was followed by echocardiographic measurements, glycemic and hemoglobulin A1c profiling, immunoblot, qPCR, enzyme activity assays, and immunohistochemistry (IHC) analysis of DPPI, ISPs, and inflammatory markers. Fibrosis was determined from left ventricular heart by Serius Red staining and qPCR. Apoptosis was determined by TUNEL assay and immunoblot analysis.RESULTS: In the diabetic WT mice, DPPI expression increased along with ISP activation, and DPPI accumulated abundantly in the left ventricle mainly from infiltrating neutrophils. In diabetic DPPI-knockout (DPPI-KO) mice, significantly decreased activation of ISPs, myocyte apoptosis, fibrosis, and cardiac function was improved compared to diabetic WT mice. In addition, DPPI-KO mice showed a decrease in overall inflammatory status mediated by diabetes induction which was manifested by decreased production of pro-inflammatory cytokines like TNF-alpha, IL-1beta and IL-6.CONCLUSION: This study elucidates a novel role of ISPs in potentiating the immunological responses that lead to the pathogenesis of DCM in T1DM. To the best of our knowledge, this is the first study to report that DPPI expression and activation promotes the inflammation that enhances myocyte apoptosis and contributes to the adverse cardiac remodeling that subsequently leads to DCM.