Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Int J Mol Sci. 2023 Jul 10;24(14):11284. doi: 10.3390/ijms241411284.
Patients with obstructive sleep apnea (OSA) exhibit a high prevalence of pulmonary hypertension and right ventricular (RV) hypertrophy. However, the exact molecule responsible for the pathogenesis remains unknown. Given the resistance to RV dilation observed in transient receptor potential canonical 3 mice during a pulmonary hypertension model induced by phenylephrine (PE), we hypothesized that TRPC3 also plays a role in chronic intermittent hypoxia (CIH) conditions, which lead to RV dilation and dysfunction. To test this, we established an OSA mouse model using 8- to 12-week-old 129/SvEv wild-type and mice in a customized breeding chamber that simulated sleep and oxygen cycles. Functional parameters of the RV were evaluated through analysis of cardiac cine magnetic resonance images, while histopathological examinations were conducted on cardiomyocytes and pulmonary vessels. Following exposure to 4 weeks of CIH, mice exhibited significant RV dysfunction, characterized by decreased ejection fraction, increased end-diastole RV wall thickness, and elevated expression of pathological cardiac markers. In addition, reactive oxygen species (ROS) signaling and the endothelin system were markedly increased solely in the hearts of CIH-exposed mice. Notably, no significant differences in pulmonary vessel thickness or the endothelin system were observed in the lungs of wild-type (WT) and mice subjected to 4 weeks of CIH. In conclusion, our findings suggest that TRPC3 serves as a regulator of RV resistance in response to pressure from the pulmonary vasculature, as evidenced by the high susceptibility to RV dilation in mice without notable changes in pulmonary vasculature under CIH conditions.
阻塞性睡眠呼吸暂停（OSA）患者表现出很高的肺动脉高压和右心室（RV）肥厚患病率。然而，确切的致病分子仍然未知。鉴于在苯肾上腺素（PE）诱导的肺动脉高压模型中，瞬时受体电位经典型 3 型（TRPC3）小鼠对 RV 扩张的抵抗力，我们假设 TRPC3 在导致 RV 扩张和功能障碍的慢性间歇性低氧（CIH）条件下也发挥作用。为了验证这一点，我们使用定制的饲养室在 8-12 周龄的 129/SvEv 野生型和 TRPC3 敲除（KO）小鼠中建立了 OSA 模型，该饲养室模拟了睡眠和氧气循环。通过心脏电影磁共振图像分析评估 RV 的功能参数，同时对心肌细胞和肺血管进行组织病理学检查。在接受 4 周 CIH 暴露后，TRPC3 KO 小鼠表现出明显的 RV 功能障碍，特征为射血分数降低、舒张末期 RV 壁厚度增加和病理性心脏标志物表达增加。此外，ROS 信号和内皮素系统仅在 CIH 暴露的 TRPC3 KO 小鼠心脏中明显增加。值得注意的是，在接受 4 周 CIH 的野生型（WT）和 TRPC3 KO 小鼠的肺部，肺血管厚度或内皮素系统没有明显差异。总之，我们的研究结果表明，TRPC3 作为 RV 对肺血管压力的抵抗调节剂，在 CIH 条件下，TRPC3 KO 小鼠对 RV 扩张的高度易感性而肺血管无明显变化。
