Early Hyperlipidemia Promotes Endothelial Activation via a Caspase-1-Sirtuin 1 Pathway

Objective - The role of receptors for endogenous metabolic danger signals-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation. Approach and Results - Using biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)^-/-/caspase-1^-/- double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE^-/- mouse aorta; (2) caspase-1^-/-/ApoE^-/- mice attenuated early atherosclerosis; (3) caspase-1^-/-/ApoE^-/- mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1^-/-/ApoE^-/- mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE^-/- aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway. Conclusions - Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations.