Proteolysis sensitizes LDL particles to phospholipolysis by secretory phospholipase A2 group V and secretory sphingomyelinase

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

“…The latter include lipolysis of polar lipids, such as phosphatidylcholine or sphingomyelin, and proteolysis of apoB followed by dissociation of its proteolytic fragments (7)(8)(9)(10)(11)(12)(13)(14)(15)32 ). We showed that thermal denaturation 2 mimics in vivo LDL aggregation, fusion, and rupture (i.e., release of neutral lipids from LDL core, which coalesces into droplets) ( 30 ) (supplementary Fig.…”

“…Although the detailed structural basis for LDL fusion is unclear, it is thought to result from accumulation of packing defects on LDL surface that form upon mechanical, thermal, chemical or enzymatic perturbations (9)(10)(11)(12)(13)(14)(15)(29)(30)(31)(32). The latter include lipolysis of polar lipids, such as phosphatidylcholine or sphingomyelin, and proteolysis of apoB followed by dissociation of its proteolytic fragments (7)(8)(9)(10)(11)(12)(13)(14)(15)32 ).…”

“…In atherosclerosis, LDL lipids are deposited in the arterial intima; according to the response-to-retention paradigm ( 4, 5 ), LDL retention by the arterial matrix proteoglycans triggers a cascade of pro-atherogenic events culminating in formation of atherosclerotic plaque ( 6-8 ). These events include biochemical modifi cations of LDL, such as oxidation and/or hydrolysis by the resident proteases and lipases, e.g., phospholipase A 2 and sphingomyelinase, which can reduce LDL affi nity for the LDL receptor, increase LDL affi nity for the proteoglycans, and promote LDL fusion (7)(8)(9)(10)(11)(12)(13)(14). In addition, ionic interactions with proteoglycans reduce LDL stability and promote their fusion and rupture (i.e., release of core lipids) ( 15 ).…”

Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH

“…In some experiments, LDL was proteolyzed with ␣ -chymotrypsin (SigmaAldrich) or pronase E (Sigma-Aldrich) either before or after bcSMase treatment ( 10 ). In addition, in some experiments, the incubation mixture contained monoclonal antibodies (Bsol 2, Bsol 14: 0.36 mg/ml).…”

Acidification of the intimal fluid: the perfect storm for atherogenesis

“…Acidic proteases, such as cathepsins, are found extracellularly in normal and atherosclerotic intima, and they efficiently proteolyze apoB-100 leading to LDL particle fusion (79)(80)(81). Moreover, proteolysis of apoB-100 sensitizes the LDL particles to lipases, thereby promoting their lipolytic modification ( 82,83 ). Interestingly, activated macrophages secrete cathepsins together with H + ions and so, by acidifying their local microenvironment, provide optimal conditions for activity of these secreted proteases ( 84 ).…”