Folks, we’ve got a big problem here. These large necrotic cores, they’re causing vulnerable atherosclerotic plaques. And you know what that means? Severe cardiovascular diseases. But the big question is, how does this happen? We don’t know yet, but we’re on it.

We’ve been looking at the expression levels of key proteins, comparing different stages of plaques in humans and mice. We’ve been doing luciferase assays, loss-of-function studies, all to figure out how microRNA protects foamy macrophages from necroptotic cell death. We’ve even used a knockout mouse model with perivascular drug administration and tail vein injection of microRNA inhibitors in Apoe^-/- mice. We’re doing everything we can.

And you know what we found? The necroptotic pathway, not the apoptotic or pyroptotic, is more activated in advanced unstable plaques. This is big. It’s closely linked with necrotic core formation. We also found that the upregulated expression of Ripk3 promotes the C/EBPβ-dependent transcription of the microRNA miR-223 to 3p. This inhibits Ripk3 expression and forms a negative feedback loop to regulate the necroptosis of foamy macrophages.

We also found that knocking out the Mir223 gene in bone marrow cells speeds up atherosclerosis in Apoe^-/- mice. But this can be fixed by Ripk3 deficiency or treatment with the necroptosis inhibitors necrostatin-1 and GSK-872. Treating Apoe^-/- mice with miR-223 to 3p inhibitors also increases atherosclerosis.

So, what’s the takeaway? miR-223 to 3p expression in macrophages protects against atherosclerotic plaque rupture by limiting the formation of necrotic cores. This could be a game changer, a potential microRNA therapeutic candidate for atherosclerosis. We’re making progress, folks. We’re getting closer to the answers.