Proteolysis sensitizes LDL particles to phospholipolysis by secretory phospholipase A2 group V and secretory sphingomyelinase.
LDL particles that enter the arterial intima become exposed to proteolytic and lipolytic modifications. The extracellular hydrolases potentially involved in LDL modification include proteolytic enzymes, such as chymase, cathepsin S, and plasmin, and phospholipolytic enzymes, such as secretory phospholipases A2 (sPLA2-IIa and sPLA2-V) and secretory acid sphingomyelinase (sSMase). Here, LDL was first proteolyzed and then subjected to lipolysis, after which the effects of combined proteolysis and lipolysis on LDL fusion and on binding to human aortic proteoglycans (PG) were studied. Chymase and cathepsin S led to more extensive proteolysis and release of peptide fragments from LDL than did plasmin. sPLA2-IIa was not able to hydrolyze unmodified LDL, and even preproteolysis of LDL particles failed to enhance lipolysis by this enzyme. However, preproteolysis with chymase and cathepsin S accelerated lipolysis by sPLA2-V and sSMase, which resulted in enhanced fusion and proteoglycan binding of the preproteolyzed LDL particles. Taken together, the results revealed that proteolysis sensitizes the LDL particles to hydrolysis by sPLA2-V and sSMase. By promoting fusion and binding of LDL to human aortic proteoglycans, the combination of proteolysis and phospholipolysis of LDL particles potentially enhances extracellular accumulation of LDL-derived lipids during atherogenesis.
Plihtari
Riia
R
Wihuri Research Institute, Helsinki, Finland.
Hurt-Camejo
Eva
E
Oörni
Katariina
K
Kovanen
Petri T
PT
D001011:Aorta / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D053818:Chymases / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D054505:Group V Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008066:Lipolysis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010316:Particle Size; D011509:Proteoglycans / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
D008077:Lipoproteins, LDL; D011509:Proteoglycans; D054505:Group V Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase; D002403:Cathepsins; D053818:Chymases; D005341:Fibrinolysin; C028217:cathepsin S