Abstract：
Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial hypertrophy and fibrosis. A growing number of studies have shown that mitochondria-associated endoplasmic reticulum membranes (MAMs) are involved in various physiological and pathological processes, such as calcium homeostasis, lipid metabolism, inflammatory response, mitochondrial dynamics, and autophagy/mitophagy. The abnormal expression of MAMs-related factors is closely related to the occurrence and development of heart-related diseases. However, the role of MAM-related factors in the maladaptive RV remodeling of PH rats remains unclear.
We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy.
The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.
We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy.
The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.
摘要：
背景：适应性不良右心室（RV）重塑是肺动脉高压（PH）的最重要病理特征，涉及心肌肥大和纤维化等过程。越来越多的研究表明,线粒体相关内质网膜(MAMs)参与各种生理和病理过程,比如钙稳态，脂质代谢，炎症反应，线粒体动力学，和自噬/线粒体自噬。MAMs相关因子的异常表达与心脏相关疾病的发生发展密切相关。然而,MAM相关因子在PH大鼠适应不良RV重塑中的作用尚不清楚。
结果：我们首先从基因表达综合（GEO）数据库中获得了Su5416联合缺氧治疗（SuHx）诱导的PH大鼠RV组织的转录组数据。结果表明,两个MAMs相关基因(Opa1和Mfn2)在SuHx大鼠RV组织中显著下调,伴随着心脏肥大相关基因(如Nppb和Myh7)的显著上调。随后，使用SuHx诱导的PH大鼠模型，我们发现线粒体融合蛋白Opa1和Mfn2的下调可能通过加速线粒体功能障碍而参与适应不良RV重塑。最后,在细胞水平上，我们发现Opa1和Mfn2的过表达可以抑制缺氧诱导的H9c2心肌细胞线粒体裂变和减少ROS的产生,从而延缓心肌细胞肥大的进展。
结论：线粒体融合蛋白Opa1/Mfn2表达下调可加速SuHx诱导的PH大鼠心肌细胞肥大，进而参与适应型RV重塑。这可能是预防适应不良RV重塑的潜在目标。
结果：我们首先从基因表达综合（GEO）数据库中获得了Su5416联合缺氧治疗（SuHx）诱导的PH大鼠RV组织的转录组数据。结果表明,两个MAMs相关基因(Opa1和Mfn2)在SuHx大鼠RV组织中显著下调,伴随着心脏肥大相关基因(如Nppb和Myh7)的显著上调。随后，使用SuHx诱导的PH大鼠模型，我们发现线粒体融合蛋白Opa1和Mfn2的下调可能通过加速线粒体功能障碍而参与适应不良RV重塑。最后,在细胞水平上，我们发现Opa1和Mfn2的过表达可以抑制缺氧诱导的H9c2心肌细胞线粒体裂变和减少ROS的产生,从而延缓心肌细胞肥大的进展。
结论：线粒体融合蛋白Opa1/Mfn2表达下调可加速SuHx诱导的PH大鼠心肌细胞肥大，进而参与适应型RV重塑。这可能是预防适应不良RV重塑的潜在目标。
