The molecular mechanism of direct cardiotoxicity of cannabinoid, and the effect of ethanol

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K19483
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 58040:Forensics medicine-related
• Research Institution: The University of Tokyo (2020-2022); Tokyo Medical and Dental University (2019)
• Principal Investigator: Noritake Kanako 東京大学, 大学院医学系研究科(医学部), 特任研究員 (40758067)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: Δ9-THC / ERストレス / マクロピノサイトーシス / AMPK / 心筋細胞

Outline of Final Research Achievements

Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive constituent of marijuana, has been reported to induce adverse effects on the cardiovascular system, including arrhythmias and myocardial infarctions. The aim of this study is to examine the mechanism of direct cardiotoxicity of Δ9-THC. Alcohol (ethanol) can increase the risk of developing cardiovascular disease caused by Δ9-THC; therefore, the effect of ethanol on Δ9-THC cytotoxicity was also examined. Δ9-THC induced apoptosis caused by ER stress in HL-1 murine cardiomyocyte. We also observed cytoplasmic vacuolization through enhanced macropinocytosis, a process involved in the uptake of extracellular fluids including nutrients. Moreover Δ9-THC activated AMPK, a sensor of intracellular energy status and an activator of macropinocytosis. AMPK activation involved not only in the induction of macropinocytosis but also in cytoprotection against Δ9-THC cytotoxicity.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

近年、世界的に大麻乱用者は増加しているが、大麻使用による身体への影響について科学的証明は十分されていないのが現状である。本研究では、Δ9-THCの心毒性の発現機構を分子レベルで明らかにしたことで、大麻使用にリスクが伴う可能性があることを認識する一助となると考える。