Electrical Remodeling in Right Ventricular Failure Due to Pulmonary Hypertension: Unraveling Novel Therapeutic Targets

被引:1
|
作者
Park, John F. [1 ]
Liang, Justine [1 ]
Umar, Soban [1 ]
机构
[1] Univ Calif Los Angeles, Dept Anesthesiol & Perioperat Med, Los Angeles, CA 90095 USA
关键词
right ventricle; pulmonary hypertension; arrhythmia; ion channel; RNA sequencing; transcriptome; drug repurposing; Sugen-hypoxia; monocrotaline; HEART; ARRHYTHMIAS; CHANNELS;
D O I
10.3390/ijms24054633
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 K-V and K-ir 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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页数:10
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