Atherosclerosis Regression Mechanisms in Diabetic Models

In diabetes, sustained hyperglycaemia and altered lipid metabolism conspire to impede the natural resolution of atherosclerotic plaques. Regression of atherosclerosis entails coordinated processes that remove lipid‐laden foam cells, dampen inflammation and restore arterial integrity. In diabetic models, advanced glycation end‐products engage the receptor for advanced glycation end‐products (RAGE) on macrophages, sustaining pro‐inflammatory programmes and impairing emigration from the lesion. Epigenetic modifications arising from high glucose exposure further entrench a pro‐atherogenic phenotype by repressing genes essential for cholesterol efflux and anti‐inflammatory activation. Central to regression is the transition of macrophages towards a reparative state, characterised by enhanced efferocytosis of apoptotic cells, upregulation of chemokine receptor CCR7 and activation of nuclear receptors such as the Liver X receptor (LXR). These pathways promote transcription of cholesterol transporters, notably ATP‐binding cassette transporter A1 (ABCA1), and support reverse cholesterol transport to the liver. In diabetic milieus, reduced expression of key chromatin modifiers and diminished responsiveness to pro‐resolution cytokines conspire to blunt regression. Therapeutically, targeting RAGE signalling, restoring epigenetic regulators and selectively activating LXR‐driven programmes hold promise for reinstating the balance between lesion progression and resolution, with potential to reduce cardiovascular risk in diabetes.

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Atherosclerosis Regression Mechanisms in Diabetic Models publication trend

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Technical terms

Atherosclerosis regression: The process by which lipid-rich arterial plaques diminish in size and inflammatory activity, restoring vessel function.

Foam cell: A lipid‐engorged macrophage within the arterial wall that contributes to plaque formation and stability.

Efferocytosis: The clearance of apoptotic cells by phagocytes, essential for resolving inflammation in plaques.

Cholesterol efflux: The removal of excess cholesterol from cells to extracellular acceptors, a critical step in reverse cholesterol transport.

RAGE: Receptor for advanced glycation end‐products, a cell surface receptor that sustains inflammatory signalling in diabetic complications.

Interferon regulatory factor 7 (IRF7): A transcription factor driving type I interferon responses in immune cells.

ATP‐binding cassette transporter A1 (ABCA1): A membrane protein that mediates the export of cellular cholesterol to lipid acceptors.

Liver X receptor (LXR): A nuclear receptor that senses cellular sterol levels and induces expression of genes involved in cholesterol transport and efflux.

References

1. RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and cholesterol metabolism. JCI Insight (2020).
2. LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2. PLOS ONE (2015).
3. Monocytes and Macrophages as Protagonists in Vascular Complications of Diabetes. Frontiers in Cardiovascular Medicine (2020).
4. Regression of Atherosclerosis Is Characterized by Broad Changes in the Plaque Macrophage Transcriptome. PLOS ONE (2012).