siRNA Targeting ECE-1 Partially Reverses Pulmonary Arterial Hypertensionassociated Damage in a Monocrotaline Model.

Citlali Margarita Blancas-Napoles, Sandra Edith Cabrera-Becerra, Vivany Maydel Sierra-Sánchez, Sergio Adrian Ocampo-Ortega, Vanessa Giselle Garcia-Rubio, Rodrigo Romero-Nava, Fengyang Huang, Enrique Hong, Asdrúbal Aguilera-Méndez, Santiago Villafaña
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Abstract

Aims: The aim of this study was to develop a possible treatment for pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterised by a pulmonary arterial pressure greater than 20 mmHg. One of the factors that contribute to PAH is an increase in the production of endothelin-1, a polypeptide that increases vascular resistance in the pulmonary arteries, leading to increased pulmonary arterial pressure and right ventricular hypertrophy.

Objective: The objective of this study was to design, synthesize, and evaluate two siRNAs directed against endothelin-1 in a rat model of PAH induced with monocrotaline.

Methods: Wistar rats were administered monocrotaline (60 mg/kg) to induce a PAH model. Following two weeks of PAH evolution, the siRNAs were administered, and after two weeks, right ventricular hypertrophy was evaluated using the RV/LV+S ratio, blood pressure, weight, and relative expression of ECE-1 (Endothelin-converting enzyme-1) mRNA (messenger RNA) by RT-PCR (real-time PCR).

Results: The monocrotaline group showed an increase in the hypertrophy index and in ECE-1 mRNA, as well as a significant decrease in weight compared to the control group, while in the monocrotaline + siRNA group, a significant decrease was observed in the relative expression of ECE-1 mRNA, as well as in right ventricular hypertrophy.

Conclusions: Based on the above information, we conclude that the administration of siRNAs directed to ECE-1 decreases the damage associated with PAH.

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靶向 ECE-1 的 siRNA 部分逆转单克隆模型中与肺动脉高压相关的损伤
目的:本研究旨在开发一种治疗肺动脉高压的可行方法:肺动脉高压(PAH)是一种罕见的疾病,其特征是肺动脉压力超过 20 mmHg。导致 PAH 的因素之一是内皮素-1(一种增加肺动脉血管阻力的多肽)的分泌增加,从而导致肺动脉压升高和右心室肥大:本研究的目的是设计、合成和评估两种针对内皮素-1 的 siRNA,并将其应用于用单克 罗林诱导的 PAH 大鼠模型中:方法:给 Wistar 大鼠注射单氯他林(60 毫克/千克)诱导 PAH 模型。方法:给 Wistar 大鼠注射单氯肾上腺素(60 毫克/千克)诱导 PAH 模型,在 PAH 演变两周后注射 siRNAs,两周后用 RV/LV+S 比值、血压、体重和 RT-PCR(实时 PCR)检测 ECE-1(内皮素转换酶-1)mRNA(信使 RNA)的相对表达来评估右心室肥大:结果:与对照组相比,单克洛他林组的肥厚指数和ECE-1 mRNA均有所增加,体重也显著下降;而在单克洛他林+siRNA组,ECE-1 mRNA的相对表达量和右心室肥厚均显著下降:根据上述信息,我们得出结论:服用针对 ECE-1 的 siRNA 可减少 PAH 引起的损伤。
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