Abstract Body (Do not enter title and authors here): Background
Atherosclerosis plaque rupture is the pathological basis and chief culprit of most acute cardiovascular events and death. Emerging evidence suggests that prekallikrein plays an important role in the pathogenesis of atherosclerosis including control of coagulation, complement, and inflammation processes, and regulation of cholesterol levels. However, little is known about the modulation mechanisms of prekallikrein in atherosclerotic plaque stability.
Method
We divided 120 ACS patients into those with and without plaque rupture (PR and non-PR, respectively) based on optical coherence tomography image analysis, and quantified the patients' serum prekallikrein levels. Next, we engineered KLKB1 deficient mice (Klkb1^-/-Apoe^-/-) and a murine atherosclerosis model with vulnerable plaques was induced with high-cholesterol diet and perivascular carotid collar placement surgeries in Apoe^-/- mice. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. Finally, we further investigated the role and mechanism of prekallikrein in smooth muscle cells and macrophages phenotype switching, proliferation and migration by in vitro experiments.
Result
The serum prekallikrein levels of PR patients is significantly higher than that of non-PR patients, and significantly correlated with the thickness of the fibrous cap of the plaque and the length and arc of the lipids. which may be an effective predictor of PR. On a high-fat diet, Klkb1^-/-Apoe^-/- mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis and phenotypic changes of smooth muscle cells are inhibited in the plaques of Klkb1^-/-Apoe^-/- mice. In vitro, Klkb1 deficiency inhibits ox-LDL-induced macrophage autophagy and the smooth muscle cells phenotype switching, proliferation and migration.
Conclusion
In the present work, we uncover a crucial role for prekallikrein in atherosclerosis as an important regulator of macrophage apoptosis and macrophages phenotype switching and subsequently atherosclerotic plaque destabilization. Cumulatively, these results suggest that targeting prekallikrein may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.