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Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC
Khatuna Gabunia1, Allison B Herman1, Mitali Ray1
1Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
Abstract:
The transformation of vascular smooth muscle cells [VSMC] into foam cells leading to increased plaque size and decreased stability is a key, yet understudied step in atherogenesis. We reported that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine, attenuates atherosclerosis by anti-inflammatory effects on VSMC. In this work we report that IL-19 induces expression of miR133a, a muscle-specific miRNA, in VSMC. Although previously unreported, we report that miR133a can target and reduce mRNA abundance, mRNA stability, and protein expression of Low Density Lipoprotein Receptor Adaptor Protein 1, (LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the Autosomal Recessive Hypercholesterolemia (ARH) disorder in humans. Herein we show that IL-19 reduces lipid accumulation in VSMC, and LDLRAP1 expression and oxLDL uptake in a miR133a-dependent mechanism. We show that LDLRAP1 is expressed in plaque and neointimal VSMC of mouse and human injured arteries. Transfection of miR133a and LDLRAP1 siRNA into VSMC reduces their proliferation and uptake of oxLDL. miR133a is significantly increased in plasma from hyperlipidemic compared with normolipidemic patients. Expression of miR133a in IL-19 stimulated VSMC represents a previously unrecognized link between vascular lipid metabolism and inflammation, and may represent a therapeutic opportunity to combat vascular inflammatory diseases.
Insights
Interleukin-19 (IL-19) reduces lipid accumulation in vascular smooth muscle cells (VSMC) by inducing miR133a. This process downregulates Low Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1), offering a potential therapeutic target for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Atherosclerosis Research
Background:
- Vascular smooth muscle cell (VSMC) transformation into foam cells is critical in atherogenesis.
- Interleukin-19 (IL-19), an anti-inflammatory cytokine, has shown potential in attenuating atherosclerosis.
- The precise mechanisms by which IL-19 affects VSMC in atherogenesis require further elucidation.
Purpose of the Study:
- To investigate the role of IL-19 in regulating VSMC lipid metabolism and foam cell formation.
- To identify downstream molecular targets of IL-19 in VSMC relevant to atherosclerosis.
- To explore the potential of the IL-19/miR133a/LDLRAP1 axis as a therapeutic strategy for vascular inflammatory diseases.
Main Methods:
- VSMC culture and treatment with IL-19.
- Quantitative PCR and Western blotting to assess gene and protein expression (miR133a, LDLRAP1).
- Measurement of lipid accumulation and oxidized LDL (oxLDL) uptake in VSMC.
- Transfection studies with miR133a mimics and LDLRAP1 siRNA.
- Analysis of LDLRAP1 expression in human and mouse arterial tissues.
- Plasma miR133a level assessment in hyperlipidemic and normolipidemic patients.
Main Results:
- IL-19 induces the expression of miR133a in VSMC.
- miR133a directly targets and reduces LDLRAP1 mRNA and protein levels.
- IL-19 reduces lipid accumulation and oxLDL uptake in VSMC via a miR133a-dependent mechanism.
- LDLRAP1 is expressed in VSMC within atherosclerotic plaques and neointima.
- miR133a levels are elevated in plasma of hyperlipidemic patients.
Conclusions:
- IL-19 exerts anti-atherogenic effects by promoting miR133a expression in VSMC.
- The miR133a-mediated downregulation of LDLRAP1 impacts vascular lipid metabolism.
- This pathway represents a novel link between inflammation and lipid regulation in VSMC.
- Targeting the IL-19/miR133a/LDLRAP1 axis may offer a therapeutic avenue for atherosclerosis and related vascular diseases.
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