Insulin Receptors in Vascular Smooth Muscle Cells Regulate Plaque Stability of Atherosclerosis
Research Background
Cardiovascular diseases (CVD) are one of the leading causes of death worldwide, particularly among patients with diabetes and insulin resistance, where the risk of CVD is significantly elevated. Although the prognosis for diabetic patients has improved in recent years, their CVD-related mortality rate remains 2 to 7 times higher than that of non-diabetic individuals of the same age. Atherosclerosis is one of the primary pathological bases of CVD, and the instability of plaques is a key factor leading to acute cardiovascular events such as myocardial infarction and stroke. Unstable plaques are typically characterized by thin fibrous caps, reduced vascular smooth muscle cells (VSMCs), decreased extracellular matrix (ECM), and increased inflammation. However, the mechanisms by which insulin resistance and diabetes contribute to plaque instability have not been fully elucidated.
The role of insulin in vascular endothelial cells and smooth muscle cells has been extensively studied, but the specific role of insulin receptors (IRs) in vascular smooth muscle cells and their impact on the stability of atherosclerotic plaques remains unclear. Therefore, this study aims to investigate the role of insulin receptors in vascular smooth muscle cells and the mechanisms by which they regulate the stability of atherosclerotic plaques.
Research Source
This study was conducted by Qian Li, Jialin Fu, Kyoungmin Park, Hetal Shah, Qin Li, I-Hsien Wu, and George L. King from the Vascular Cell Biology Laboratory at the Joslin Diabetes Center, Harvard Medical School. The research was published online on August 28, 2024, in the journal Cardiovascular Research.
Research Process and Results
1. Animal Model Construction and Experimental Design
The research team constructed various mouse models, including double knockout mice for ApoE and IR genes (SMIRKO/ApoE−/−), Myh11-CreERT2EYFP+/ApoE−/− mice, and Myh11-CreERT2EYFP+IRKO/ApoE−/− mice. These models were used to study the specific role of insulin receptors in vascular smooth muscle cells. By inducing insulin resistance through a high-fat diet (HFD), the researchers compared the characteristics of atherosclerotic plaques in different mouse models.
2. Insulin Signaling and Plaque Stability
The study found that the area of atherosclerotic plaques was significantly increased in SMIRKO/ApoE−/− mice, with reduced vascular smooth muscle cells and collagen content in the plaques, along with increased apoptosis and necrotic areas. Using lineage tracing techniques, the researchers discovered that vascular smooth muscle cells lacking insulin receptors exhibited higher expression of inflammatory markers (such as ICAM1 and VCAM1), indicating that these cells had more inflammatory properties.
3. Cell Culture and Molecular Mechanism Studies
In vitro experiments, vascular smooth muscle cells were isolated from the aortas of ApoE−/− and SMIRKO/ApoE−/− mice and cultured. The experiments showed that cells lacking insulin receptors expressed higher levels of inflammatory cytokines (such as IL-6 and CCL2). Further research revealed that insulin inhibited apoptosis and promoted proliferation of vascular smooth muscle cells by activating the IR/AKT signaling pathway, and this effect was significantly weakened in SMIRKO/ApoE−/− mice.
4. Insulin’s Regulation of Inflammation and ECM
The researchers also found that insulin inhibited the expression of Thrombospondin 1 (THBS1) through the AKT/FOXO1 signaling pathway, and the absence of THBS1 reduced the expression of inflammatory cytokines. Additionally, THBS1 induced the expression of MMP2, a key enzyme responsible for ECM degradation. Therefore, insulin influenced the inflammatory response and ECM stability of plaques by regulating the expression of THBS1 and MMP2.
Research Conclusion
This study demonstrates that insulin plays a crucial role in vascular smooth muscle cells through its receptors, reducing inflammation, apoptosis, and ECM degradation, thereby enhancing the stability of atherosclerotic plaques. The weakening of insulin signaling due to insulin resistance and diabetes may promote the formation of unstable plaques by increasing inflammation and ECM degradation. This finding provides a new mechanistic explanation for understanding how insulin resistance and diabetes increase the risk of cardiovascular diseases.
Research Highlights
- First to Reveal the Anti-inflammatory Role of Insulin Receptors in Vascular Smooth Muscle Cells: The study found that insulin receptors inhibit the expression of inflammatory cytokines through the AKT/FOXO1 signaling pathway, thereby reducing the inflammatory response in plaques.
- Elucidated the Key Role of THBS1 and MMP2 in Plaque Stability: The research showed that insulin regulates the expression of THBS1 and MMP2, affecting the stability of ECM and the inflammatory response in plaques.
- Provides New Insights for Treating Diabetes-Related Cardiovascular Diseases: The findings offer a theoretical basis for developing novel therapeutic strategies targeting the insulin signaling pathway, potentially helping to reduce the risk of cardiovascular events in diabetic patients.
Research Significance
This study not only reveals the important role of insulin receptors in vascular smooth muscle cells but also provides new mechanisms for understanding how insulin resistance and diabetes lead to plaque instability. These findings offer a significant theoretical foundation for developing novel treatments targeting the insulin signaling pathway, potentially helping to reduce the risk of cardiovascular diseases in diabetic patients. Additionally, the research highlights the critical role of THBS1 and MMP2 in plaque stability, providing potential targets for future drug development.
Other Valuable Information
The research team also analyzed the gene expression profiles of vascular smooth muscle cells in atherosclerotic plaques using single-cell RNA sequencing, further validating the key role of THBS1 and MMP2 in plaque inflammation and ECM degradation. These data provide a rich resource for future research, aiding in the further exploration of the molecular mechanisms of atherosclerosis.