Hydrogen-generated metal-organic framework nanoparticles for ameliorated pulmonary hypertension by ROS scavenging, hydrogen anti-inflammation, and reducing DNA damage

Abstract

Pulmonary hypertension (PH) is a malignant and progressive disease lacking effective treatments, characterized primarily by pulmonary vascular remodeling resulting from endothelial cells (ECs) dysfunction. The increase of reactive oxygen species (ROS) in a pathological state is the pivotal factor that triggers ECs dysfunction, primarily through the induction of DNA damage. Currently, there is a significant scarcity of drugs capable of reducing ECs DNA damage by eliminating ROS in the microenvironment. Therefore, we synthesis hydrogen-generated metal-organic framework nanoparticles (PdH/ZIF-8), which can not only release hydrogen continuously for over 24 h, but also has efficiently ROS scavenging activity. In vitro, PdH/ZIF-8 inhibits hypoxia-induced dysfunction of pulmonary microvascular ECs. In vivo models PdH/ZIF-8 accumulates in lungs rapidly and steadily, effectively alleviating pulmonary vascular remodeling, and ultimately significantly improving cardiac function. Further, PdH/ZIF-8 decreases expression of inflammatory factors. At the same time, PdH/ZIF-8 regulates the expression of poly ADP-ribose polymerase (PARP1), reduced ataxia telangiectasia mutated and Rad3 related (ATR)/cell cycle checkpoint kinase 1 (CHK1) phosphorylation. In conclusion, this work provides a novel and effective nanotechnology with the synergistic therapy of innocuous gas to the treatment of PH.