Doja Qaraqe

Introduction. Coronary artery disease (CAD) is a leading cause of death in individuals over 35 years¹. Stents are a standard line of care to open occluded arteries in CAD patients². Stents are susceptible to in-sent restenosis (ISR), which is re-narrowing of the artery after stent placement. ISR is diagnosed by narrowing of greater than 50% of the stent lumen and acute coronary syndromes³. The driving mechanism behind ISR is neointimal hyperplasia and vascular smooth muscle (VSMC) proliferation due to endothelial damage during stent placement^5,6,9. Current treatments of ISR like scoring balloon angioplasty and drug-eluting stents pose major problems like thrombosis and inconsistent drug delivery^3,4. Alternatively, there is therapeutic potential in targeting Mfn2, which is heavily involved in ISR. Methods. Many studies were required to elucidate the role of Mfn2 in ISR. The effects of Mfn2 were tested in rodent models, where ISR was induced by endothelial injury and the effect on VSMC were subsequently observed. Homocysteine has been implicated to silence Mfn2, therefore many studies explored Mfn2 in high homocysteine environments⁵. Immunofluorescence and western blot were used to determine the relationship between Mfn2 methylation, c-Myc (transcription factor), and DNMT2 (DNA methyltransferase)⁵. DAPI/TUNEL immunofluorescence and ELISA quantified VSMC death in Mfn2-treated cells⁶. Vessel staining demonstrated Mfn2’s effect on pro-apoptotic and anti-proliferative proteins in VSMC cells. Carotid artery denudation injuries in rodents treated with Mfn2 highlighted the role of miRNA-93 in ISR⁷. Abdominal aorta transplantation in rodents underlined the role of TGF-b and its polymorphisms in ISR. Results. Overexpression of Mfn2 in high homocysteine led to increased Edu+ (cell death) aortic root cells⁵. Homocysteine upregulated c-Myc and DNMT2, which increased Mfn2 methylation, thus silencing the gene⁵. Mfn2 inhibits growth pathways like MAPK/PI3K to reduce VSMC proliferation and neointimal hyperplasia⁶. Mfn2 promotes apoptosis by upregulating pro-apoptotic proteins like BAX and caspase-3⁶. MiRNA-93 downregulates Mfn2 by binding to and downregulating the gene. High circulating levels of miRNA-93 were implicated in ISR patients⁸. TGF-β promotes fibrogenesis to increase intimal thickness. TGF-β is inversely related to Mfn2⁹. TGF-β polymorphisms were linked to increased ISR risk^9,10. Conclusion. These experiments established a molecular pathway regulating ISR and defined Mfn2’s role in ISR. Mfn2 has pro-apoptotic and anti-proliferative effects to reduce VSMC proliferation and neointimal hyperplasia^5,7. MiRNA-93 promotes ISR by downregulating Mfn2⁷. TGF-β promotes ISR by inducing vessel thickening. Mfn2 or any of its upstream/downstream effects may be exploited therapeutically to lower the risk of ISR improve disease prognosis.

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