Elucidation of the mechanism of pulmonary hypertension induced by repeated cocaine administration

2023 Fiscal Year Final Research Report

• Project/Area Number: 23K19799
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0908:Society medicine, nursing, and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: WEN Shuheng 東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (80981779)
• Project Period (FY): 2023-08-31 – 2024-03-31
• Keywords: コカイン / 血管毒性 / ミトコンドリア分裂 / DRP1 / HIF-1α

Outline of Final Research Achievements

Long-term cocaine abuse is associated with cardiovascular and pulmonary vascular complications. The vascular toxicity of cocaine can lead to vascular remodeling characterized by excessive proliferation of vascular smooth muscle cells. Though HIF signaling and mitochondrial fission have been suggested to play essential roles in the pathogenesis of hypoxia-induced vascular remodeling, pathogenetic mechanism for cocaine-related vascular remodeling remains to be elucidated. In this study, we explore the effect of cocaine on the proliferation of vascular smooth muscle cells by in vitro experiments. The findings indicated that the cocaine-induced vascular smooth muscle cell hyperproliferation is achieved by enhancing DRP1-mediated mitochondrial fission and activating HIF-1α signaling. Current findings suggested that mitochondrial fission would play a pivotal role in cocaine-related vascular remodeling and would be helpful in understanding the vascular toxicity of cocaine.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

肺高血圧症の発症機序の解析はここ数年の間に長足の進歩を遂げているが、いまだにコカインによる肺高血圧の発症機序はまだ解明されていない。我々はコカインの長期投与が酸化ストレス/HIF-1α/DRP1依存性ミトコンドリア分裂経路を介して血管平滑筋細胞の過剰増殖を引き起こすことを示された。コカインによる酸化ストレスに起因するDRP1依存性ミトコンドリア分裂の活性化が、コカインによる肺高血圧症の発症機序と明らかになった。この機序の解明は、コカインによる肺高血圧症に対する理解の空白を埋めることになり、コカイン肺毒性に新たな知見を与えることになると考えられる。