Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and-9

Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor a (TNF alpha)-stimulated proinflammatory responses, in particular activation of nuclear factor-kappa B and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNF alpha-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis. Laboratory Investigation (2012) 92, 236-245; doi:10.1038/labinvest.2011.154; published online 31 October 2011