Background: Pulmonary arterial hypertension is a potentially fatal condition with no effective cure. Recent studies have shown that progressively increasing pulmonary vascular resistance and irreversible pulmonary vascular remodeling are key factors contributing to pulmonary hypertension. Methyltransferase like 3 (METTL3), a key N6-Methyladenosine (m6A) methyltransferase, it has been shown that elevated levels of METTL3 expression is a risk factor for pulmonary hypertension, Elevated levels of METTL3 contribute to vascular remodeling in the lungs, resulting in increased pulmonary artery pressure and right ventricular hypertrophy. Methods: To obtain a model of pulmonary hypertension, we placed C57BL/6 male mice in a 500-liter ventilated room with a 10% oxygen concentration for four weeks. After mice were placed in a hypoxic incubator for two weeks, they were started on intraperitoneal injections of STM2457 once a day for two weeks, after which right ventricular pressure was measured using a Miller catheter, right ventricular remodeling is determined using hematoxylin-eosin staining, right ventricular hypertrophy was assessed using the right ventricular/left ventricular + septum (RV/LV+S) ratio and relative expression of TNF-α, IL-1β, IL-6 protein by western blot. The impact of STM2457 on Human Pulmonary Artery Smooth Muscle Cells (HPASMCs) under hypoxia was examined by evaluating their viability, proliferation, migration and the expression of IL-1β, IL-6, and TNF-α proteins. Results: In mouse models of hypoxic PAH, METTL3 expression was significantly increased and pulmonary vascular remodeling. Treatment with STM2457 significantly decreased right ventricular pressure and hypertrophy, and inhibited molecules associated with the inflammation signaling pathway. Additionally, the inhibition of METTL3 by STM2457 attenuated hypoxia-induced proliferation and migration of HPASMCs, while further inhibiting molecules associated with the inflammation signaling pathway. Conclusions: Based on the results obtained above, we are confident that treatment with STM2457 targeting METTL3 significantly reduces damage in PAH model mice and cells.
Content Details:-
Corresponding author: Hui Li**
Full Length Article: Inhibitor Targeting METTL3 Partially Reverses Damage Associated with Pulmonary Arterial Hypertension in Mouse and Cell Models
Journal: Austin Journal of Nutrition & Metabolism
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