Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China.
Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150086, People's Republic of China.
Cardiovasc Toxicol. 2021 Dec;21(12):965-972. doi: 10.1007/s12012-021-09687-6. Epub 2021 Sep 14.
Human immunodeficiency virus (HIV) infection is a risk factor of cardiovascular diseases (CVDs). HIV-infected patients exhibit cardiac dysfunction coupled with cardiac fibrosis. However, the reason why HIV could induce cardiac fibrosis remains largely unexplored. HIV-1 trans-activator of transcription (Tat) protein is a regulatory protein, which plays a critical role in the pathogenesis of various HIV-related complications. In the present study, recombinant Tat was administered to mouse myocardium or neonatal mouse cardiac fibroblasts in different doses. Hematoxylin-eosin and Masson's trichrome staining were performed to observe the histological changes of mice myocardial tissues. EdU staining and MTS assay were used to evaluate the proliferation and viability of neonatal mouse cardiac fibroblasts, respectively. Real-time PCR and western blot analysis were used to detect CTGF, TGF-β1, and collagen I mRNA and protein expression levels, respectively. The results showed that Tat promoted the occurrence of myocardial fibrosis in mice. Also, we found that Tat increased the proliferative ability and the viability of neonatal mouse cardiac fibroblasts. The protein and mRNA expression levels of TGF-β1 and CTGF were significantly upregulated both in Tat-treated mouse myocardium and neonatal mouse cardiac fibroblasts. However, co-administration of TGF-β inhibitor abrogated the enhanced expression of collagen I induced by Tat in neonatal mouse cardiac fibroblasts. In conclusion, Tat contributes to HIV-related cardiac fibrosis through enhanced TGF-β1-CTGF signaling cascade.
人类免疫缺陷病毒（HIV）感染是心血管疾病（CVDs）的一个风险因素。感染 HIV 的患者表现出心脏功能障碍和心脏纤维化。然而，HIV 为何会导致心脏纤维化的原因在很大程度上仍未得到探索。HIV-1 转录激活物（Tat）蛋白是一种调节蛋白，在各种与 HIV 相关的并发症的发病机制中起着关键作用。在本研究中，以不同剂量将重组 Tat 给予小鼠心肌或新生小鼠心肌成纤维细胞。通过苏木精-伊红和 Masson 三色染色观察小鼠心肌组织的组织学变化。通过 EdU 染色和 MTS 测定分别评估新生小鼠心肌成纤维细胞的增殖和活力。通过实时 PCR 和 Western blot 分析分别检测 CTGF、TGF-β1 和胶原 I 的 mRNA 和蛋白表达水平。结果表明 Tat 促进了小鼠心肌纤维化的发生。此外，我们发现 Tat 增加了新生小鼠心肌成纤维细胞的增殖能力和活力。Tat 处理的小鼠心肌和新生小鼠心肌成纤维细胞中 TGF-β1 和 CTGF 的蛋白和 mRNA 表达水平均显著上调。然而，TGF-β 抑制剂的共同给药消除了 Tat 诱导的新生小鼠心肌成纤维细胞中胶原 I 的增强表达。总之，Tat 通过增强 TGF-β1-CTGF 信号级联促进与 HIV 相关的心脏纤维化。
