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Updated: Jun 15, 2025
Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
Insulin receptors in vascular smooth muscle cells regulate plaque stability of atherosclerosis
Qian Li1,2, Jialin Fu1,2, Kyoungmin Park1,2
1Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Aims:
Increased prevalence of acute myocardial infarction related to diabetes and insulin resistance is associated with an elevated risk of unstable atherosclerotic plaques, which are characterized by reduced vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) and increased inflammation. Thus, insulin resistance may reduce plaque stability, as deleting insulin receptors (IRs) in VSMCs decreases their proliferation and enhances apoptosis.
Methods And Results:
Direct effects of insulin on VSMCs to alter plaque composition were studied using mice with double knockout of ApoE and IR genes in VSMCs with SMIRKO/ApoE-/-, Myh11-CreERT2EYFP+/ApoE-/-, and Myh11-CreERT2EYFP+IRKO/ApoE-/- mice, which were also used for lineage tracing studies. Compared with ApoE-/- mice, SMIRKO/ApoE-/- mice exhibited more atherosclerotic plaques, which contained less VSMCs and collagen but increased levels of VSMC apoptosis and necrotic areas. Lineage tracing studies showed that Icam1+ Vcam1+ VSMC was inflammatory, which increased in the aortas of Myh11-CreERT2EYFP+IRKO/ApoE-/- mice compared with control mice. Isolated VSMCs lacking IRs expressed higher inflammatory cytokines than cells with IRs. Cell-based studies indicated that insulin's anti-apoptotic and pro-proliferative effects in VSMCs were mediated via activation of the IR/Akt pathway, which were decreased in VSMCs from SMIRKO or high-fat diet mice. An analysis of the IR targets that regulated inflammatory cytokines in VSMCs showed that thrombospondin 1 (Thbs1) and Mmp2 were consistently increased with a loss of IRs. Insulin inhibited Thbs1 expression, but not Mmp2 expression, through p-Akt/p-FoxO1 pathways in VSMCs from ApoE-/- mice, and was impaired in cells from SMIRKO/ApoE-/- mice. Thbs1 further induced Icam1 and Mmp2 expressions in VSMCs.
Conclusion:
Insulin via IRs has significant actions in VSMCs to decrease inflammation, apoptosis, and ECM turnover via the activation of Akt and FoxO1 pathways. The inhibition of insulin actions and related pathways related to insulin resistance and diabetes may contribute to the formation of unstable atherosclerotic plaques.
Insights
Insulin resistance promotes unstable atherosclerotic plaques by impairing vascular smooth muscle cell (VSMC) function. Loss of insulin receptors (IRs) in VSMCs increases inflammation and apoptosis, contributing to plaque instability.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Atherosclerosis Pathogenesis
Background:
- Diabetes and insulin resistance are linked to increased acute myocardial infarction and unstable atherosclerotic plaques.
- Vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) are reduced, while inflammation is increased in unstable plaques.
- Insulin resistance may compromise plaque stability by affecting VSMC proliferation and apoptosis.
Purpose of the Study:
- To investigate the direct effects of insulin on VSMCs and their role in altering atherosclerotic plaque composition.
- To elucidate the molecular mechanisms by which insulin signaling in VSMCs influences plaque stability.
Main Methods:
- Utilized genetically modified mice (SMIRKO/ApoE-/-, Myh11-CreERT2EYFP+/ApoE-/-, and Myh11-CreERT2EYFP+IRKO/ApoE-/-) for in vivo studies and lineage tracing.
- Examined atherosclerotic plaque characteristics, including VSMC content, collagen levels, apoptosis, and necrotic areas.
- Conducted in vitro studies on isolated VSMCs to assess inflammatory cytokine expression and insulin signaling pathways (IR/Akt/FoxO1).
Main Results:
- Mice lacking insulin receptors (IRs) in VSMCs exhibited larger atherosclerotic plaques with reduced VSMCs and collagen, increased apoptosis, and necrotic areas.
- Loss of IRs in VSMCs led to increased expression of inflammatory markers (Icam1, Vcam1) and cytokines.
- Insulin's anti-apoptotic and pro-proliferative effects on VSMCs, mediated by the IR/Akt pathway, were diminished in IR-deficient VSMCs and those from high-fat diet-fed mice.
- Thrombospondin 1 (Thbs1) and Mmp2 were upregulated in IR-deficient VSMCs; insulin inhibited Thbs1 via Akt/FoxO1, an effect impaired in IR-deficient cells.
Conclusions:
- Insulin signaling through IRs in VSMCs is crucial for suppressing inflammation, apoptosis, and ECM turnover via Akt and FoxO1 activation.
- Impaired insulin signaling, as seen in insulin resistance and diabetes, contributes to the development of unstable atherosclerotic plaques.
- Targeting insulin signaling pathways in VSMCs may offer a therapeutic strategy for stabilizing atherosclerotic plaques.
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