Rana Indrajeetsinh, Kompa Andrew R, Skommer Joanna, Wang Bing H, Lekawanvijit Suree, Kelly Darren J, Krum Henry, Charchar Fadi J
School of Health Sciences Federation University Australia, Ballarat, Victoria, Australia.
Centre of Cardiovascular Research and Education in Therapeutics Monash University, Melbourne, Victoria, Australia Department of Medicine, University of Melbourne St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Physiol Rep. 2015 Apr;3(4). doi: 10.14814/phy2.12371.
Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and microRNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis.
心肌梗死（MI）患者肾功能的进行性下降与循环中尿毒症毒素水平升高有关，这会导致细胞外基质沉积增加。我们最近报道，用尿毒症毒素吸附剂AST - 120治疗心肌梗死大鼠可抑制尿毒症毒素硫酸吲哚酚（IS）的血清水平，并下调心脏促纤维化细胞因子转化生长因子β（TGF - β1）的表达。在本研究中，我们研究了心肌梗死后尿毒症毒素对心脏微小RNA - 21和微小RNA - 29b表达的影响，以及参与TGFβ1和血管紧张素II信号通路的靶基因和基质重塑蛋白的调控。心肌梗死后16周，评估心脏组织的病理和分子变化。在接受载体处理的心肌梗死大鼠组中，心脏纤维化面积百分比为4.67±0.17，假手术组为2.9±0.26，接受AST - 120处理的心肌梗死大鼠组为3.32±0.38。与假手术组相比，我们发现接受载体处理的心肌梗死大鼠心脏组织中微小RNA - 21的表达增加了两倍，微小RNA - 29b的表达减少了0.5倍。用AST - 120治疗可降低血清IS水平，并减轻心肌梗死后观察到的心脏纤维化和这些微小RNA表达的变化。我们还发现，从心肌梗死大鼠收集的心脏组织中血管紧张素转换酶（ACE）和血管紧张素受体1a（Agtr1a）的mRNA表达增加。用AST - 120治疗可减轻ACE和Agtr1a mRNA的表达。将大鼠心脏成纤维细胞暴露于IS可上调血管紧张素II信号通路，并改变微小RNA - 21和微小RNA - 29b的表达。这些结果共同表明，IS通过涉及血管紧张素信号通路的机制，在改变心肌梗死心脏中的微小RNA - 21和微小RNA - 29b方面具有明确作用，这会导致心脏纤维化。
