Electrical Remodeling in Right Ventricular Failure Due to Pulmonary Hypertension: Unraveling Novel Therapeutic Targets.
Electrical Remodeling in Right Ventricular Failure Due to Pulmonary Hypertension: Unraveling Novel Therapeutic Targets.
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DOI：
10.3390/ijms24054633
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发表时间：
2023-02-27
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
右心室（RV）重构背景下的心律失常是肺动脉高压患者死亡的主要原因。然而，电重构的潜在机制仍然难以捉摸，尤其是室性心律失常。在这里，我们分析了肺动脉高压（PAH）患者代偿性RV或失代偿性RV的RV转录组，并确定了8个和45个差异表达基因，这些基因分别参与调节心肌细胞兴奋和收缩的电生理特性。在患有失代偿性RV的PAH患者中，编码电压门控Ca2+和Na+通道的转录本明显减少，同时KV和Kir通道也明显失调。我们进一步发现RV通道组特征与两种已知的PAH动物模型，单氯胆碱（MCT）和缺氧糖（SuHx）处理的大鼠相似。我们在MCT、SuHx和PAH失代偿性RV衰竭患者中确定了15个共同的转录本。此外，数据驱动的药物再利用利用PAH失代偿性RV衰竭患者的通道体特征预测了可能逆转基因表达改变的候选药物。对比分析为心律失常发生机制的临床相关性和潜在的临床前治疗研究提供了进一步的见解。
Arrhythmias in the setting of right-ventricular (RV) remodeling contribute to majority of deaths in patients with pulmonary hypertension. However, the underlying mechanism of electrical remodeling remains elusive, especially ventricular arrhythmias. Here, we analyzed the RV transcriptome of pulmonary arterial hypertension (PAH) patients with compensated RV or decompensated RV and identified 8 and 45 differentially expressed genes known to be involved in regulating the electrophysiological properties of excitation and contraction of cardiac myocytes, respectively. Transcripts encoding voltage-gated Ca2+ and Na+ channels were notably decreased in PAH patients with decompensated RV, along with significant dysregulation of KV and Kir channels. We further showed similarity of the RV channelome signature with two well-known animal models of PAH, monocrotaline (MCT)- and Sugen-hypoxia (SuHx)-treated rats. We identified 15 common transcripts among MCT, SuHx, and PAH patients with decompensated RV failure. In addition, data-driven drug repurposing using the channelome signature of PAH patients with decompensated RV failure predicted drug candidates that may reverse the altered gene expression. Comparative analysis provided further insight into clinical relevance and potential preclinical therapeutic studies targeting mechanisms involved in arrhythmogenesis.
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影响因子：
39.3
作者：
Humbert, Marc;Kovacs, Gabor;Wort, Stephen John
通讯作者：
Wort, Stephen John
影响因子：
5.5
作者：
Reilly L;Eckhardt LL
通讯作者：
Eckhardt LL
影响因子：
6
作者：
Sánchez J;Trenor B;Saiz J;Dössel O;Loewe A
通讯作者：
Loewe A
影响因子：
6
作者：
Shah K;Seeley S;Schulz C;Fisher J;Gururaja Rao S
通讯作者：
Gururaja Rao S
DOI：
10.1038/s44161-022-00113-w
发表时间：
2022-08-01
期刊：
NATURE CARDIOVASCULAR RESEARCH
影响因子：
--
作者：
Boucherat, Olivier;Yokokawa, Tetsuro;Bonnet, Sebastien
通讯作者：
Bonnet, Sebastien