Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway

Background: Rhodiola crenulata is traditionally used as a folk medicine in Tibet for preventing high-altitude illnesses, including sudden cardiac death (SCD). The cardio-protective effects of Rhodiola crenulata root extract (RCE) against hypoxia in vivo have been recently confirmed. However, the way in which RCE produces these effects remains unclear. The present study is designed to confirm the protective effects of RCE on the heart in acute hypobaric hypoxia exposure and examine the mechanisms by which this occurs. Methods: Sprague-Dawley (SD) rats were pretreated with or without RCE and then exposed to a simulated altitude of 8000 m in a hypobaric hypoxia chamber for 9 h. The expression of cardiac arginase 1 (Arg-1) and endothelial nitric oxide synthase (eNOS) and the activity of associated signaling pathways was examined. Results: Hypoxia reduced cardiac eNOS phosphorylation and increased Arg-1 expression, but both responses were reversed by RCE pre-treatment. In addition, RCE decreased the hypoxia-induced oxidative stress markers of reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and protein carbonyl content. Furthermore, RCE protected cardiomyocytes from hypoxia-induced cardiac apoptosis and restored the phosphorylation level of AKT and p38 MAPK as well as the superoxide dismutase 2 (SOD2) content in hypoxic animals. Conclusion: The findings provide evidence that the effects of Rhodiola crenulata against altitude illness are partially mediated by modulation of eNOS and Arg-1 pathways in the heart.