Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway

Area of Science:

• Cardiovascular Biology
• Immunology
• Metabolic Disease Research

Background:

• Endothelial cells (ECs) are the first to encounter circulating danger signals.
• The role of ECs in sensing hyperlipidemia and initiating inflammation is not well understood.
• Caspase-1 is a key mediator in innate immune responses to danger signals.

Purpose of the Study:

• To investigate if caspase-1 plays a role in endothelial cells sensing hyperlipidemia.
• To determine if caspase-1 activation in ECs promotes EC activation and early atherosclerosis.
• To elucidate the molecular pathway involved in hyperlipidemia-induced EC activation.

Main Methods:

• Utilized apolipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice.
• Employed biochemical, immunologic, and pathological analyses.
• Performed bone marrow transplantation studies.

Main Results:

• Early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta.
• ApoE(-/-)/caspase-1(-/-) mice showed attenuated atherosclerosis, reduced proinflammatory cytokines, and decreased monocyte recruitment.
• Oxidized lipids activated caspase-1 and promoted pyroptosis in ECs via reactive oxygen species; caspase-1 inhibition increased sirtuin 1, which downregulated caspase-1 via the activator protein-1 pathway.

Conclusions:

• Early hyperlipidemia activates ECs before monocyte recruitment through a caspase-1-sirtuin 1-activator protein-1 pathway.
• This finding provides insight into novel therapeutics for early intervention in metabolic cardiovascular diseases.
• Targeting caspase-1 activation offers a potential strategy for managing hyperlipidemia-induced inflammation.