P J van Santbrink

Publications (2)11.62 Total impact

• Source

  Available from: Ilze Bot

  Article: Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis.

  R de Nooijer, I Bot, J H von der Thüsen, M A Leeuwenburgh, H S Overkleeft, A O Kraaijeveld, R Dorland, P J van Santbrink, S H van Heiningen, M M Westra, P T Kovanen, J W Jukema, E E van der Wall, Th J C van Berkel, G P Shi, E A L Biessen
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  ABSTRACT: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability.
  Arteriosclerosis Thrombosis and Vascular Biology 01/2009; 29(2):188-94. · 6.37 Impact Factor
• Article: Design and synthesis of novel amphiphilic dendritic galactosides for selective targeting of liposomes to the hepatic asialoglycoprotein receptor.

  L A Sliedregt, P C Rensen, E T Rump, P J van Santbrink, M K Bijsterbosch, A R Valentijn, G A van der Marel, J H van Boom, T J van Berkel, E A Biessen
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  ABSTRACT: A series of glycolipids have been prepared which contain a cluster galactoside moiety with high affinity for the hepatic asialoglycoprotein receptor and a bile acid ester moiety which mediates stable incorporation into liposomes. Loading of liposomes with these glycolipids at a ratio of 5% (w/w) resulted in efficient recognition and uptake of the liposomes by the liver. Preinjection with asialofetuin almost completely inhibited the uptake, establishing that the liposomes were selectively recognized and processed by the asialoglycoprotein receptor on liver parenchymal cells. In contrast, a glycolipid content of 50% (w/w) led to a liver uptake that could not be inhibited by preinjection with asialofetuin, indicating that the liposomes were now processed by the Gal/Fuc-recognizing receptor on liver macrophages. The results presented in this study are important for future targeting of water-soluble and amphiphilic drugs, enveloped in these glycolipid-laden liposomes, to parenchymal liver cells.
  Journal of Medicinal Chemistry 03/1999; 42(4):609-18. · 5.25 Impact Factor