Atherosclerotic Plaque Reduction in Mice via Itaconate Delivered into Immune Cells
Researchers here find a way to reduce atherosclerotic plaque in mice by delivering an anti-inflammatory metabolite associated with low fat diets directly to immune cells in the bone marrow and plaque. It is an interesting result, though the degree to which it will be applicable to humans is a question. Mice are more resistant to plaque formation, requiring both high fat diets and mutations affecting cholesterol transport to produce sizable plaques. When switched to a low fat diet, there will be some degree of plaque regression in mice previously on a high fat diet - but that doesn't tend to happen in humans. Will dialing up the mechanisms involved in mouse plaque regression on a low fat diet perform to any great degree in humans? It may be worth a try, given that even very small degrees of plaque regression produce sizable reductions in risk of heart attack and stroke.
Laboratory animals that develop atherosclerotic plaque when fed a prolonged high-cholesterol, high-fat diet (HCHFD) demonstrate plaque resolution when they are subsequently switched to a normal low-fat diet ("dietary cessation"). Here, we studied dietary cessation in two well-known atherogenic mouse models: AроE-/- and Ldlr-/-. Using these models, we discovered that dietary cessation-driven plaque resolution is characterized by altered levels of the tricarboxylic acid (TCA) cycle metabolite itaconate (ITA), an immunomodulatory molecule, and of the ITA-synthesizing enzyme immunoresponsive gene 1 (IRG1). We also report elevated levels of IRG1 in vulnerable human carotid plaques and the absence of IRG1 in early or stable plaques.
We next tested whether exposing plaques to exogenously delivered ITA could directly achieve plaque resolution. While the ITA derivative 4-octyl itaconate (OI) has been previously shown to induce plaque resolution, current ITA derivatives are not ideal for studying or replicating the biological effects of endogenous, unconjugated ITA, which differs from its derivatives. Thus, to achieve targeted and efficient delivery of unconjugated ITA, we synthesized an ITA-based lipid nanoparticlen.wikipedia.org/wiki/Solid_lipid_nanoparticle">lipid nanoparticle, termed ITA-LNP. We demonstrate that ITA-LNPs deliver unconjugated ITA intracellularly, accumulate in myeloid cells in plaque and bone marrow, and recapitulate immunomodulatory effects that are unique to unmodified ITA. We also show that ITA-LNPs are non-toxic and elicit epigenetic changes that lead to anti-inflammatory activity in plaques and myeloid progenitor cells in bone marrow. Additionally, we report that ITA-LNPs safely stimulate plaque resolution in several murine models with and without dietary cessation, including a model of unstable, vulnerable plaque that represents highly advanced atherosclerotic cardiovascular disease.