Cardiovascular Implications of Cannabis Use: Unravelling the Molecular and Cellular Dynamics of THC Metabolites
Tez Türü: Doktora
Tezin Yürütüldüğü Kurum: Kingston University, Health, Science, Social Care and Education, Molecular Biology, Biophysics and Biochemistry, İngiltere
Tez Danışmanı: Dr Brian V Rooney
Tezin Onay Tarihi: 2024
Tezin Dili: İngilizce
Desteklendiği Program: Diğer
Özet:
Worldwide, cannabis is the second most utilised recreational drug after alcohol. This research investigates the effects of Δ-9 tetrahydrocannabinol (THC) and its primary metabolites, 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), on cardiac cells and tissues. Through a combination of in vitro experiments on rat cardiomyocyte cells (H9c2) and human cardiac fibroblasts (HCFs), in vivo studies with the planarian model Polycelis nigra, and a meta-analysis of cannabis users, this research offers novel insights into the cellular and molecular mechanisms of cannabis-induced cardiotoxicity and tissue remodelling. Additionally, it includes the first UK-based epidemiological analysis of postmortem cannabis concentrations in relation to cardiac risk factors from the National Programme of Substance Abuse Deaths (NPSAD) over a 20-year period.
The findings demonstrate that THC metabolites induce significant cellular changes in cardiomyocytes and cardiac fibroblasts, including microstructural alterations, increased cell migration, proliferation, and extracellular matrix (ECM) deposition. These effects are linked to the activation of the PI3K/AKT and ERK/MAPK pathways, suggesting their potential involvement in THC metabolite-induced cardiac hypertrophy and fibrosis. This research also elucidates the role of microtubule dynamics in the alteration of cell polarity and subsequent ECM deposition in response to cannabinoid metabolites. In vivo studies demonstrated a dose-dependent effect of THC metabolites on tissue changes, with low doses enhancing tissue deposition and high doses resulting in toxicity. Co-treatment with the PI3K inhibitor LY294002 significantly reduced these effects, underscoring the importance of the PI3K/AKT pathway.
Complementing the laboratory studies, the meta-analysis revealed a significant association between cannabis use and cardiovascular events, including myocardial infarction. The epidemiological study, examining THC-COOH concentrations in postmortem blood samples, suggests that even occasional cannabis use can significantly alter cardiac tissue, potentially contributing to cardiovascular complications. This research identifies the PI3K/AKT pathway and microtubule dynamics as potential targets for therapeutic intervention and underscores the need for further research into the cardiovascular consequences of cannabis use.