Melatonin activates the Mst1-Nrf2 signaling to alleviate cardiac hypertrophy in pulmonary arterial hypertension.

Among pulmonary arterial hypertension (PAH) patients, right ventricular (RV) functioning has been considered a major determining factor for cardiac capacity and survival. However, despite the recognition of the clinical importance for preserving RV functioning, no effective treatments are currently available for RV failure. This study aims to suggest one such possible treatment, through investigating the cardio-protective capabilities of the anti-oxidant, melatonin (Mel), for treating adverse RV remodeling in PAH, along with its underlying mechanisms. Arginine vasopressin induced neonatal rat cardiomyocyte hypertrophy in vitro; in vivo, PAH was induced in rats through intraperitoneal monocrotaline (MCT) injections, and Mel was administered intraperitoneally 24 h prior to MCT. Mel reduced rat cardiomyocyte hypertrophy and mitochondrial oxidative stress in vitro by activating the Mst1-Nrf2 pathway, which were all reversed upon siRNA knockdown of Mst1. Likewise, in vivo, Mel pre-treatment significantly ameliorated MCT-induced deterioration in cardiac function, RV hypertrophy, fibrosis and dilation. These beneficial effects were also associated with Mst1-Nrf2 pathway up regulation and its associated reduction in oxidative stress, as evidenced by the decrease in RV malondialdehyde content. Notably, results from Mel treatment were similar, or even superior, to those obtained from N-acetyl cysteine (NAC), which has already been-confirmed as an anti-oxidative treatment for PAH. By contrast, co-treatment with the Mst1 inhibitor XMU-MP-1 reversed all of those Mel-associated beneficial effects. Our findings thus identified Mel as a potent cardio-protective agent against the onset of maladaptive RV remodeling, through enhancement of the anti-oxidative response via Mst1-Nrf2 pathway activation.