Division of Cardiothoracic Surgery, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL, USA.
J Card Fail. 2010 Aug;16(8):628-34. doi: 10.1016/j.cardfail.2010.03.007. Epub 2010 May 4.
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 subjects.
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 1 (ACVRL1) (+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 müllerian 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).
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 are 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.
左心发育不全综合征（HLHS）的特征是左心室（LV）发育不良，以及单心室生理导致右心室（RV）的生物力学压力增加。尽管具有临床意义，但 RV 重构和疾病进展过程中活跃的信号通路尚不清楚。为了解决这个问题，我们研究了从 HLHS 患者的 RV 组织中分离出的与转化生长因子-β（TGF-β）/骨形态发生蛋白（BMP）信号相关的基因表达的差异变化，相对于对照受试者的 RV 和 LV 组织。
使用定量实时聚合酶链反应检测 6 名接受 1 期 Norwood 手术的 HLHS 新生儿（年龄 1-7 天；平均 4 天）的 RV 组织中与 TGF-β/BMP 介导的心脏发育、细胞生长和分化相关的 84 个基因的表达变化，以及从 5 名患有非心脏病理的婴儿（年龄范围 1-135 天：平均 85 天）获得的 RV 和 LV 组织作为对照。对对照-LV 和对照-RV 的基因表达谱进行分析，结果显示 RV 中 TGF-β/BMP 信号明显受到抑制。在分析的 84 个基因中，38 个在 HLHS-RV 与对照-RV 之间表达差异，而与对照-LV 相比只有 22 个。观察到明显的变化包括：组织重塑基因包括激活素受体 IIA（ACVR2A）（+2.13）和激活素受体样激酶 1（ACVRL1）（+2.22）；细胞存活、生长和分化基因包括 CDC25A（+2.18）、p21（-3.64）、p15（+2.15）、BMP5（+4.58）、BMP3（+2.16）、GDF3（+8.59）、NODAL（+2.32）和 BMP 结合内皮调节剂（BMPER）（+4.58）。HLHS-RV 与对照-RV 和对照-LV 样本组之间最显著的共同变化是抗苗勒管激素受体 2（AMHR2）（+18.79 对照-RV，+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）。
尽管这项描述性研究不允许进行因果推断，但我们的结果表明，HLHS 患儿新生儿 RV 中的心脏发育途径发生变化，并上调与细胞生长和分化相关的基因。这些分子谱与在相似成熟年龄的正常 LV 中观察到的更为密切相关，而不是正常 RV。这项工作为阐明 HLHS 中 RV 重构的分子机制提供了未来机制研究的基础。
