Physiologisches Institut, Justus-Liebig-Universität, 35392 Gießen, Germany.
Excellence Cluster Cardiopulmonary System (ECCPS), Justus-Liebig-Universität, 35392 Gießen, Germany.
Int J Mol Sci. 2024 Jun 5;25(11):6212. doi: 10.3390/ijms25116212.
Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.
活性氧(ROS)的产生增加对于肺动脉高压(PH)期间右心室(RV)肥大(RVH)和衰竭(RVF)的发展很重要。ROS 分子在细胞内的不同隔室中产生,已知线粒体产生最强的 ROS 信号。在形成 ROS 的线粒体蛋白中,位于外线粒体膜的单胺氧化酶(MAO,A 型或 B 型)能够降解神经递质,从而产生大量的 ROS。在小鼠中,MAO-B 是主要同工酶,存在于心脏内几乎所有细胞类型中。我们分析了诱导型心肌细胞特异性 MAO-B 敲除(cmMAO-B KO)对小鼠 RVH 和 RVF 发展的影响。通过肺动脉结扎(PAB)诱导 RVH。通过超声心动图测量 RV 尺寸和功能。通过二氢乙啶染色评估 ROS 产生、蛋白激酶活性(PamStation 设备)和全身血液动力学(体内导管插入术)。与 Cre-阴性同窝仔鼠相比,cmMAO-B KO 小鼠在 PAB 期间 ROS 形成显著减少,这与参与肥大生长的蛋白激酶活性降低有关。与 PAB 后 RV 扩张和肥大的同窝仔鼠相反,cmMAO-B KO 小鼠对 PAB 的 RV 尺寸无反应,并且在 cmMAO-B KO 小鼠中未测量到 PAB 期间同窝仔鼠中可见的 RV 收缩功能下降。总之,与同窝仔鼠相比,cmMAO-B KO 小鼠在 RV 压力超负荷后可防止 RV 扩张、肥大和功能障碍。这些结果支持 cmMAO-B 是 PH 期间导致 RV 肥大和衰竭的关键因素的假说。