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Cardiovascular disease remains the leading cause of death worldwide, characterized by atherosclerotic activity within large and medium‐sized arteries. Inflammation has been shown to be a primary driver of atherosclerotic plaque formation, with interleukin‐1 (IL‐1) having a principal role. This review focuses on the current state of knowledge of molecular mechanisms of IL‐1 release from cells in atherosclerotic plaques. A more in‐depth understanding of the process of IL‐1's release into the vascular environment is necessary for the treatment of inflammatory disease processes, as the current selection of medicines being used primarily target IL‐1 after it has been released. IL‐1 is secreted by several heterogenous mechanisms, some of which are cell type–specific and could provide further specialized targets for therapeutic intervention. A major unmet challenge is to understand the mechanism before and leading to IL‐1 release, especially by cells in atherosclerotic plaques, including endothelial cells, vascular smooth muscle cells, and macrophages. Data so far indicate a heterogeneity of IL‐1 release mechanisms that vary according to cell type and are stimulus‐dependent. Unraveling this complexity may reveal new targets to block excess vascular inflammation.

Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE −/− ) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE −/− mice with macitentan, a dual ET A /ET B receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE −/− mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ET A /ET B antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE −/− mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ET A /ET B receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis.