Waddingham Mark T, Tsuchimochi Hirotsugu, Sonobe Takashi, Sequeira Vasco, Nayeem Md Junayed, Shirai Mikiyasu, Pearson James T, Ogo Takeshi
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Department of Bioregulatory Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
J Mol Cell Cardiol Plus. 2024 Mar 26;8:100072. doi: 10.1016/j.jmccpl.2024.100072. eCollection 2024 Jun.
Pulmonary hypertension (PH) often leads to right ventricle (RV) failure, a significant cause of morbidity and mortality. Despite advancements in PH management, progression to RV maladaptation and subsequent failure remain a clinical challenge. This study explored the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on RV function in a rat model of PH, hypothesizing that it improves RV function by inhibiting G protein-coupled receptor kinase 2 (GRK2) and altering myofilament protein phosphorylation.
The Su5416/hypoxia (SuHx) rat model was used to induce PH. Rats were treated with paroxetine and compared to vehicle-treated and control groups. Parameters measured included RV morphology, systolic and diastolic function, myofilament protein phosphorylation, GRK2 activity, and sympathetic nervous system (SNS) markers.
Paroxetine treatment significantly improved RV systolic function, evidenced by increased stroke volume, cardiac output, and ejection fraction, without significantly affecting RV hypertrophy, myosin heavy chain/titin isoform switching, or fibrosis. Enhanced phosphorylation of titin and myosin light chain-2 was observed, correlating positively with improved systolic function. Contrary to the hypothesis, improvements occurred independently of GRK2 inhibition or SNS modulation, suggesting an alternate mechanism, potentially involving antioxidant properties of paroxetine.
Paroxetine improves RV systolic function in PH rats, likely through mechanisms beyond GRK2 inhibition, possibly related to its antioxidant effects. This highlights the potential of paroxetine in managing RV dysfunction in PH, warranting further investigation into its detailed mechanisms of action and clinical applicability.
肺动脉高压（PH）常导致右心室（RV）衰竭，是发病和死亡的重要原因。尽管在PH管理方面取得了进展，但进展为RV适应不良及随后的衰竭仍是一项临床挑战。本研究探讨了选择性5-羟色胺再摄取抑制剂（SSRI）帕罗西汀对PH大鼠模型中RV功能的影响，假设其通过抑制G蛋白偶联受体激酶2（GRK2）和改变肌丝蛋白磷酸化来改善RV功能。
采用Su5416/低氧（SuHx）大鼠模型诱导PH。将大鼠用帕罗西汀治疗，并与用赋形剂治疗的组和对照组进行比较。测量的参数包括RV形态、收缩和舒张功能、肌丝蛋白磷酸化、GRK2活性和交感神经系统（SNS）标志物。
帕罗西汀治疗显著改善了RV收缩功能，表现为每搏输出量、心输出量和射血分数增加，而对RV肥大、肌球蛋白重链/肌联蛋白异构体转换或纤维化无显著影响。观察到肌联蛋白和肌球蛋白轻链-2的磷酸化增强，与收缩功能改善呈正相关。与假设相反，改善独立于GRK2抑制或SNS调节而发生，提示存在另一种机制，可能涉及帕罗西汀的抗氧化特性。
帕罗西汀改善了PH大鼠的RV收缩功能，可能通过GRK2抑制以外的机制，可能与其抗氧化作用有关。这突出了帕罗西汀在管理PH中RV功能障碍方面的潜力，有必要进一步研究其详细作用机制和临床适用性。
