Heparanase promotes the onset and progression of atherosclerosis in apolipoprotein E gene knockout mice

Abstract

<h3>Background and aims</h3><p>Atherosclerosis is the primary underlying cause of myocardial infarction and stroke, which are the major causes of death globally. Heparanase (Hpse) is a pro-inflammatory extracellular matrix degrading enzyme that has been implicated in atherogenesis. However, to date the precise roles of Hpse in atherosclerosis and its mechanisms of action are not well defined. This study aims to provide new insights into the contribution of Hpse in different stages of atherosclerosis <em>in vivo</em>.</p><h3>Methods</h3><p>We generated <em>Hpse</em> gene-deficient mice on the atherosclerosis-prone apolipoprotein E gene knockout (<em>ApoE</em>^−/−) background to investigate the impact of <em>Hpse</em> gene deficiency on the initiation and progression of atherosclerosis after 6 and 14 weeks high-fat diet feeding, respectively. Atherosclerotic lesion development, blood serum profiles, lesion composition and aortic immune cell populations were evaluated.</p><h3>Results</h3><p>Hpse-deficient mice exhibited significantly reduced atherosclerotic lesion burden in the aortic sinus and aorta at both time-points, independent of changes in plasma cholesterol levels. A significant reduction in the necrotic core size and increase in smooth muscle cell content were also observed in advanced atherosclerotic plaques of Hpse-deficient mice. Additionally, Hpse deficiency reduced circulating and aortic levels of VCAM-1 at the initiation and progression stages of disease and circulating MCP-1 levels in the initiation but not progression stage. Moreover, the aortic levels of total leukocytes and dendritic cells in Hpse-deficient <em>ApoE</em>^−/− mice were significantly decreased compared to control <em>ApoE</em>^−/−mice at both disease stages.</p><h3>Conclusions</h3><p>This study identifies Hpse as a key pro-inflammatory enzyme driving the initiation and progression of atherosclerosis and highlighting the potential of Hpse inhibitors as novel anti-inflammatory treatments for cardiovascular disease.</p>