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These diseases are highly associated with cigarette smoke and its key component nicotine. Here, we created a novel animal model of PH using coexposure to nicotine (or cigarette smoke) and hypoxia. This heretofore unreported model showed significant early-onset pulmonary vasoremodeling and PH. Using newly generated mice with complementary smooth muscle\u2013specific Rieske iron-sulfur protein (RISP) gene knockout and overexpression, we demonstrate that RISP is critically involved in promoting pulmonary vasoremodeling and PH, which are implemented by oxidative ataxia telangiectasia-mutated\u2013mediated DNA damage and NF-\u03baB\u2013dependent inflammation in a reciprocal positive mechanism. Together, our findings establish for the first time an animal model of hypoxia-induced early-onset PH in which mitochondrial RISP-dependent DNA damage and NF-\u03baB inflammation play critical roles in vasoremodeling. Specific therapeutic targets for RISP and related oxidative stress\u2013associated signaling pathways may create unique and effective treatments for PH, chronic obstructive pulmonary disease, and their complications.<\/jats:p>","DOI":"10.1165\/rcmb.2023-0181oc","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T15:06:46Z","timestamp":1701270406000},"page":"193-202","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":5,"title":["Rieske Iron-Sulfur Protein Mediates Pulmonary Hypertension Following Nicotine\/Hypoxia Coexposure"],"prefix":"10.1093","volume":"70","author":[{"given":"Lillian N.","family":"Truong","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ed","family":"Wilson Santos","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Min","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"key":"2026012204054196400_bib1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3390\/ijerph6010209","article-title":"Smoking and chronic obstructive pulmonary disease (COPD). 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