Rieske Iron-Sulfur Protein Mediates Pulmonary Hypertension Following Nicotine/Hypoxia Co-Exposure

Am J Respir Cell Mol Biol. 2023 Nov 29. doi: 10.1165/rcmb.2023-0181OC. Online ahead of print.ABSTRACTThe high mortality of chronic obstructive pulmonary disease (COPD) patients may occur due to pulmonary hypertension (PH). These diseases are highly associated with cigarette smoke (CS) and its key component nicotine use. Here, we created a novel animal model of PH using nicotine (or CS) and hypoxia (N/H) co-exposure. This never-reported model showed a significant early-onset pulmonary vasoremodeling and PH. Using newly-generated complementary smooth muscle (SM)-specific Rieske iron-sulfur protein (RISP) gene knockout (KO) and overexpression (OE) mice, we demonstrate that RISP is critically involved in promoting pulmonary vasoremodeling and PH, which are implemented by oxidative ataxia telangiectasia-mutated (ATM)-mediated DNA damage and NF-κB-dependent inflammation in a reciprocal positive mechanism. Together, our findings for the first time established an animal model of N/H-induced early-onset PH, where mitochondrial RISP-dependent DNA damage and NF-κB inflammation play a critical role in vasoremodeling. Specific therapeutic targets for RISP and related oxidative stress-associated signaling pathways may create unique and effective treatments for PH, COPD, and their complications.PMID:38029303 | DOI:10.1165/rcmb.2023-0181OC
Source: American Journal of Respiratory Cell and Molecular Biology - Category: Molecular Biology Authors: Source Type: research