Differential Changes in TGF-β/BMP Signaling Pathway in the Right Ventricular Myocardium of Newborns With Hypoplastic Left Heart Syndrome
Differential Changes in TGF-β/BMP Signaling Pathway in the Right Ventricular Myocardium of Newborns With Hypoplastic Left Heart Syndrome
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DOI：
10.1016/j.cardfail.2010.03.007
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发表时间：
2010-08-01
影响因子：
6
通讯作者：
Vatta, Matteo
中科院分区：
文献类型：
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作者：
Ricci, Marco;Mohapatra, Bhagyalaxmi;Vatta, Matteo
背景：左心发育不全综合征(HLHS)是以左室发育不全和右室生物力学应力增加为特征的单心室生理学疾病，其临床意义不大。RV重塑和疾病进展过程中活跃的信号通路尚不清楚。为了解决这一问题，我们检测了HLHS患者RV组织中转化生长因子-β(TGF-β)/骨形态发生蛋白(BMP)信号相关基因表达的差异，与对照组的RV和LV组织相比。方法和结果：采用实时定量聚合酶链式反应检测了参与转化生长因子-β/BMP介导的心脏发育、细胞生长的84个基因的表达变化。从6例HLHS新生儿收集的RV组织中的分化(年龄。1-7天。平均4天)和取自5名患有非心脏病变的婴儿的右室和左室组织(年龄范围。平均1-135天。在84个基因中，38个基因在HLHS-RV和对照-LV中有差异表达，而与对照-LV相比，只有22个基因在组织重塑基因中发生了显著变化，包括激活素受体IIA(ACVR2A)(+2.13)和激活素受体样激酶I(ACVRLI)(+222)，以及细胞的存活、生长。分化基因包括CDC25A(+2.18)、p21(-3)、p15(+2.15)、BMP5(+4.58)、BMP3(+2.16)、GDF3(+8.59)、Node(+2.32)和BMP结合内皮调节因子(+4.58)。+3 38对照-LV)。和BMP拮抗剂抑制素α(INHA)(+11.47对照-RV，+5.73对照-LV)结论：尽管这项描述性研究不允许因果推断，但我们的结果表明HLHS新生儿RV中心脏发育途径的改变和与细胞生长和分化相关基因的上调这些分子谱与相似成熟年龄的正常LV而不是正常RV中观察到的更密切相关。这项工作为进一步的机制研究阐明HLHS RV重构的分子机制奠定了基础(《心力衰竭杂志》2010，16 628-634)。
Background: Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of the left ventricle (LV) and increased biomechanical stress on the right ventricle (RV) from single ventricle physiology Despite the clinical significance. the signaling pathways active during RV remodeling and disease progression are not known. To address this, we examined differential changes in expression of genes associated with transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signaling in RV tissue isolated from HLHS patients relative to RV and LV tissue from control subjectsMethods and Results: Quantitative real-time polymerase chain reaction was used to detect changes in expression of 84 genes involved in TGF-beta/BMP-mediated cardiac development, cell growth. and differentiation in RV tissue collected from 6 neonates with HLHS undergoing stage 1 Norwood procedure (age. 1-7 days. mean, 4 days) and RV and LV tissue obtained from 5 infants with noncardiac pathology (age range. 1-135 days mean. 85 days) that served as controls Analysis of gene expression profiles between control-LV and control-RV revealed significant depression of TGF-beta/BMP signaling in RV compared with LV Of the 84 genes analyzed, 38 were differentially expressed between HLHS-RV and control-RV, whereas only 22 compared with control-LV Significant changes were observed in tissue remodeling genes including Activin receptor type IIA (ACVR2A) (+2.13) and Activin receptor-like kinase I (ACVRLI) (+2 22), and cell survival, growth. and differentiation genes including CDC25A (+2 18), p21 (-3 64), p15 (+2 15), BMP5 (+4 58), BMP3 (+2 16), GDF3 (+8 59), NODAL (+2 32), and BMP binding endothelial regulator (BMPER) (+4 58) The most significant changes common to HLHS-RV versus control-RV and control-LV sample groups is observed for Anti mullerian hormone receptor 2 (AMHR2) (+18.79 control-RV. +3 38 control-LV). and the BMP antagonist Inhibin alpha (INHA)(+11 47 control-RV, +5.73 control-LV)Conclusions: Although this descriptive study does not allow cause-effect inferences, our results suggest changes in cardiac development pathways and upregulation of genes associated with cell growth and differentiation in the neonatal RV of children with HLHS These molecular profiles arc more closely related to those observed in the normal LV rather than normal RV at similar maturational age This work provides the basis for future mechanistic studies to elucidate the molecular mechanisms regulating RV remodeling in HLHS (J Cardiac Fail 2010, 16 628-634)