A Non-Metallic Nanozyme Ameliorates Pulmonary Hypertension Through Inhibiting ROS/TGF-β1 Signaling.

Abstract

Pulmonary hypertension (PH) is a life-threatening cardiovascular disease with a lack of effective treatment options. Nanozymes, though promising for PH therapy, pose safety risks due to their metallic nature. Here, a non-metallic nanozyme is reported for the treatment of monocrotaline (MCT)-induced PH with a therapeutic mechanism involving the ROS/TGF-β1 signaling. The synthesized melanin-polyvinylpyrrolidone-polyethylene glycol (MPP) nanoparticles showcaseultra-small size, excellent water solubility, high biocompatibility, and remarkable antioxidant capacity. The MPP nanoparticles are capable of effectively eliminating ROS in isolated pulmonary artery smooth muscle cells (PASMCs) from PH rats, and significantly reducePASMC proliferation and migration. In vivo results from a PH model demonstratethat MPP nanoparticles significantly increasepulmonary artery acceleration time, decreasewall thickening and PCNA expression in lung tissues, as evidenced by echocardiograpy, histology and immunoblot analysis. Additionally, MPP nanoparticles treatment improverunning capacity, decreaseFulton index, and attenuateright ventricular fibrosis in MCT-PH rats by using treadmill test, picrosirius red, and trichrome Masson staining. Further transcriptomic and biochemical analyses revealthat inhibiting ROS-driven activation of TGF-β1 in the PA is the mechanism by which MPP nanoparticles exerttheir therapeutic effect. This study providesa novel approach for treating PH with non-metallic nanozymes based on a well-understood mechanism.