Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution.
Study Goal
The researchers aimed to determine the underlying mechanisms by which a low-cholesterol/low-fat diet (LCLFD) mediates plaque stabilization and inflammation reduction in atherosclerosis.
Results Summary
The study found that itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. An ITA-conjugated lipid nanoparticle was developed, which epigenetically reduced inflammation and replicated the therapeutic effects of LCLFD in multiple atherosclerosis models.
Population
Mice and humans with vulnerable plaques (myeloid cells specifically).
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
low-cholesterol/low-fat diet (LCLFD) | neutral | plaque stabilization | patients | - | mediate | #1 |
low-cholesterol/low-fat diet (LCLFD) | decrease | inflammation reduction | patients | - | mediate | #2 |
itaconate (ITA) | neutral | diet-induced plaque resolution | - | - | is key to | #3 |
immunoresponsive gene 1 (IRG1) | increase | expression in myeloid cells | vulnerable plaques in mice and humans | - | is highly elevated | #4 |
immunoresponsive gene 1 (IRG1) | decrease | expression in myeloid cells | early or stable plaques in mice and humans | - | is absent | #5 |
ITA-conjugated lipid nanoparticle | increase | plaque and bone marrow myeloid cells | - | - | accumulates in | #6 |
ITA-conjugated lipid nanoparticle | decrease | inflammation | - | - | epigenetically reduces | #7 |
ITA-conjugated lipid nanoparticle | neutral | LCLFD-induced plaque resolution | multiple atherosclerosis models | - | reproduces the therapeutic effects of | #8 |
Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models.