Heat Shock Protein Modulation in Atherosclerosis

Atherosclerosis arises from chronic inflammation and lipid accumulation within arterial walls, progressing through endothelial dysfunction, foam-cell formation and plaque development. Heat shock proteins (HSPs) constitute a conserved family of molecular chaperones that stabilise misfolded proteins, regulate proteostasis and influence key aspects of vascular biology. Certain small HSPs, such as HSP27 and HSPB1, promote endothelial survival by attenuating oxidative stress and inhibiting apoptotic pathways, while larger HSPs, including HSP60 and HSP70, play dual roles in immunomodulation and inflammatory signalling. Modulating HSP expression or activity has emerged as a strategy to tip the balance towards plaque stabilisation by reducing adhesion molecule expression, curbing macrophage lipid uptake, and enhancing smooth muscle cell resilience. The temporal context of HSP induction is critical: early upregulation can confer protection against lesion initiation, whereas late or excessive induction may exacerbate inflammatory cytokine release and foam-cell formation. Translating these insights offers the prospect of novel diagnostics and targeted therapies designed to harness the cytoprotective and immunoregulatory functions of HSPs in the prevention and treatment of cardiovascular disease.

Research from Nature Portfolio

Two independent studies have elucidated the cell-specific roles of HSP60 in atherogenesis. In one investigation, loss-of-function of endogenous HSP60 in endothelial cells attenuated oxidised low-density lipoprotein (OxLDL)-induced upregulation of adhesion molecules and preserved nitric oxide signalling, while in macrophages it altered scavenger-receptor expression, promoted OxLDL accumulation and skewed cells towards a pro-inflammatory M1 phenotype. A separate in vivo study employing apolipoprotein E–deficient mice demonstrated that induction of a broad spectrum of HSPs prior to lesion formation markedly reduced expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 in the aorta and inhibited plaque progression. Notably, initiation of HSP induction after atheroma establishment instead heightened pro-inflammatory cytokine expression and foam-cell formation, underscoring the context-dependent effects of HSP modulation on disease course.

Heat Shock Protein Modulation in Atherosclerosis publication trend

The graph below shows the total number of articles in heat shock protein modulation in atherosclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Heat shock proteins (HSPs): Conserved chaperone proteins induced by stress that assist with protein folding and protect cells from damage.

Atherosclerosis: Chronic arterial disease characterised by lipid deposition, inflammation and plaque formation in vessel walls.

Vascular smooth muscle cells (VSMCs): Muscle cells in the arterial wall that contribute to plaque structure and stability.

Oxidised low-density lipoprotein (OxLDL): Modified form of LDL cholesterol that triggers inflammation and foam-cell formation.

Intercellular adhesion molecule 1 (ICAM-1): Endothelial cell surface protein that mediates leukocyte adhesion and transmigration.

Vascular cell adhesion molecule 1 (VCAM-1): Endothelial adhesion protein facilitating monocyte attachment during vascular inflammation.

References

1. Atheroprotective Aspects of Heat Shock Proteins. International Journal of Molecular Sciences (2023).
2. HSP60 knockdown exerts differential response in endothelial cells and monocyte derived macrophages during atherogenic transformation. Scientific Reports (2021).
3. Effects from the induction of heat shock proteins in a murine model due to progression of aortic atherosclerosis. Scientific Reports (2021).
4. HSPB1 Regulates Autophagy and Apoptosis in Vascular Smooth Muscle Cells in Arteriosclerosis Obliterans. Cardiovascular Therapeutics (2022).