Abstract 5893: Pro-Atherogenic Effect of Hyaluronan Synthesis Inhibition in ApoE-Deficient Mice
Background: Hyaluronan (HA) is a prominent component of atherosclerotic and restenotic lesions. However, the function of HA in cardiovascular disease has not yet been unravelled in in vivo models. This study aimed to analyze the effect of pharmacologic inhibition of HA-synthesis by 4-methylumbelliferone (4-MU) on murine atherosclerosis.
Methods: ApoE-deficient mice on western-diet were treated with 4-MU for two, four, eleven and twenty-one weeks. Subsequently, aortic plaque score, plaque morphology and plaque composition were characterized at the aortic root. Furthermore, endothelial function was analyzed by acetylcholine dependent vasorelaxation, thrombotic response by a photochemical model of arterial thrombosis using Rose Bengal and mean arterial blood pressure by tail cuff plethysmography.
Results: HA plasma levels and HA content at the aortic root were decreased in 4-MU treated mice. Plaque burden as determined by Oil Red O was significantly increased after eleven and twenty-one weeks of 4-MU treatment. Furthermore macrophage content was also elevated at twenty-one weeks. EC50 values of acetylcholine-induced relaxation of aortic rings were significantly increased after twenty-one weeks. In parallel blood pressure was raised during 4-MU treatment. Furthermore, the thrombotic response was aggravated as evidenced by shorter times to occlusion in the thrombosis model.
Conclusion: The data suggest that chronic and systemic inhibition of HA-synthesis promotes atherogenesis which might be due to impaired endothelial function resulting in increased inflammation and elevated blood pressure.