Systemic Hyaluronan Inhibition Increases Atherosclerosis in Mice

Nagy, Nadine1, Freudenberger, Till1, Dr. Suvorava, Tatsiana2, Prof. Dr. Kojda, Georg2, Prof. Dr. Fischer, Jens W1. 1Institut für Pharmakologie Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany ; 2Institut für Pharmakologie und Klinische Pharmakologie Universitätsklinikum Düsseldorf, Heinrich-Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Background: Hyaluronan (HA) is a prominent carbohydrate component of atherosclerotic lesions. However, the function of HA in cardiovascular disease is unknown. This study aimed to analyze for the first time the effect of pharmacologic inhibition of HA-synthesis by 4-methylumbelliferone (4-MU) on murine atherosclerosis.

Methods: ApoE-deficient mice were chronically treated with 4-MU. Aortic plaque score, plaque morphology and plaque composition were characterized at the aortic root. Endothelial function was analyzed by acetylcholine dependent vasorelaxation and thrombotic response by a photochemical model of arterial thrombosis using Rose Bengal.

Results: HA plasma levels and HA content at the aortic root were decreased in 4-MU treated mice indicating effective hyaluronan synthase inhibition. Of note, plaque burden as determined by Oil Red O was significantly increased after eleven (control, 4.52 ± 0.49 % vs 4-MU, 7.36 ± 0.48 %, p<0.05) and twenty one weeks (control, 13.33 ± 2.62 % vs 4-MU, 19.98 ± 1.41 %, p<0.05) of 4-MU treatment. In parallel macrophage content was also elevated at twenty one weeks. EC50 values for acetylcholine-induced relaxation of aortic rings were significantly increased after twenty one weeks (control, 76.87 ± 12 nM vs 4-MU, 189.8 ± 42 nM, p<0.05). In parallel blood pressure was raised during 4-MU treatment (control, 110.5 ± 3.8 mmHg vs 4-MU, 122.9 ± 2.2 mmHg, p<0.05). Furthermore, the thrombotic response was aggravated as evidenced by shorter times to occlusion in the thrombosis model (control, 37.57 ± 5.6 min vs 4-MU, 23.89 ± 3.2 min, p<0.05).

Conclusion: Therefore, 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.