MnTBAP reduces pulmonary vascular remodeling in experimental pulmonary arterial hypertension

Rationale: Multiple mechanisms have been discovered underlying the pathogenesis of pulmonary arterial hypertension (PAH), including reactive oxygen species (ROS), inflammation and reduced bone morphogenic protein receptor (BMPR)2. MnTBAP can mimic the effects of manganese-superoxide dismutase to reduce ROS. Moreover, MnTBAP can reduce inflammation in endothelial cells via up-regulation of BMPR2. Collectively, we hypothesized that MnTBAP can be used to treat PAH. Methods: Experimental PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 followed by 4-weeks hypoxia and 2-weeks normoxia. At week 6, animals were randomized to receive either saline or MnTBAP until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10. Heart and lung tissues were collected. Results: MnTBAP reduced RV afterload and total pulmonary resistance in SuHx rats. Moreover, MnTBAP improved RV function by increasing stroke volume and TAPSE, as well as reducing RV end diastolic diameter and stiffness. Further tissue analysis by histology revealed that MnTBAP reduced pulmonary vascular remodeling by reducing both intima and media layer thickness. Conclusion: MnTBAP treatment can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH. Together with the improved cardiac function, MnTBAP may be a promising intervention for PAH.