Atherosclerosis

1995

DOI: 10.1016/0021-9150(95)05604-1

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Secretory group II phospholipase A2 in human atherosclerotic plaques

Mario Menschikowski¹,

²

,

et al.

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Discussion2

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Szmitko Et Al Inflammation and Endothelial Cell Activation 20431

See P 8841

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Cited by 121 publications

(57 citation statements)

References 39 publications

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“…Because the arterial intima has been shown to contain snpPLA 2 , [22][23][24][25][26] and both LDL-like particles and lipid droplets 10,43 isolated from atherosclerotic lesions show signs of phospholipid hydrolysis, we suggest that the present results can be extrapolated to the actual events in the arterial intima. snpPLA 2 is found in the intimas of even early atherosclerotic lesions 24 -26 and is occasionally found in nonatherosclerotic intimas containing considerable macrophage infiltration.…”

Section: Discussionmentioning

confidence: 77%

“…Recently, type II secretory nonpancreatic phospholipase A 2 (snpPLA 2 ), which is capable of lipolyzing LDL, 21 has been shown to be located in both atherosclerotic and nonatherosclerotic arterial intima [22][23][24][25][26] and to be associated with extracellular matrix structures and lipid droplets. 24 Interestingly, lipolysis of LDL by bee venom PLA 2 reduces the size of the LDL particles in the absence of glycosaminoglycans (GAGs) 17,20,27 but increases their size in the presence of heparin-GAG.…”

Section: See P 884mentioning

confidence: 99%

See 1 more Smart Citation

Lipolysis of LDL by Human Secretory Phospholipase A ₂ Induces Particle Fusion and Enhances the Retention of LDL to Human Aortic Proteoglycans

¹

,

²

,

³

et al. 2001

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Abstract-The first morphological sign of atherogenesis is the accumulation of extracellular lipid droplets in the proteoglycan-rich subendothelial layer of the arterial intima. Secretory nonpancreatic phospholipase A 2 (snpPLA 2 ), an enzyme capable of lipolyzing LDL particles, is found in the arterial extracellular matrix and in contact with the extracellular lipid droplets. We have recently shown that in the presence of heparin, lipolysis of LDL with bee venom PLA 2 induces aggregation and fusion of the particles. Here, we studied the effect of human snpPLA 2 on the integrity of LDL particles and on their interaction with human aortic proteoglycans. In addition, the capacity of the proteoglycans to retain PLA 2 -lipolyzed LDL particles was tested in a microtiter well assay. We found that lipolysis of LDL induced fusion of proteoglycan-bound LDL particles, which increased their binding strength to the proteoglycans. Moreover, lipolysis of LDL with snpPLA 2 under physiological salt and albumin concentrations induced a 3-fold increase in the amount of LDL bound to proteoglycans. The results imply a role for PLA 2 in the retention and accumulation of LDL to the proteoglycan matrix in atherosclerosis. Key Words: phospholipases Ⅲ LDL Ⅲ fusion Ⅲ retention Ⅲ proteoglycans I nitiation of atherosclerosis in both humans 1 and experimental animals 2-4 is characterized by the appearance of extracellular lipid droplets in the proteoglycan (PG)-rich subendothelial layer. Experimental models have shown that similar droplets can be formed directly from LDL particles both in situ 2,5 and in vivo. 2,6 Moreover, both chemical analyses 7,8 and measurements of the size 9,10 of the extracellular lipid droplets in human arterial lesions suggest that the majority of the droplets originate from LDL particles. Because native LDL particles do not fuse into such lipid droplets, the LDL particles must undergo modification in the arterial intima. Indeed, the lipid droplets isolated from the arterial intima have features suggesting that they may have been derived from plasma LDL by extensive modification (reviewed by Öörni et al 11 ). Modification of LDL in vitro by proteolytic enzymes, 12-14 by oxidative compounds, 15 or by lipolytic enzymes such as sphingomyelinase, 13,15-17 phospholipase C, 18,19 or phospholipase A 2 (PLA 2 ) 17,20 has been shown to induce aggregation, fusion, or both aggregation and fusion of the particles. See p 884Phospholipase A 2 s are enzymes that catalyze the hydrolysis of the sn-2 fatty acyl ester bond in phospholipids, yielding a free fatty acid and a lysophospholipid. Recently, type II secretory nonpancreatic phospholipase A 2 (snpPLA 2 ), which is capable of lipolyzing LDL, 21 has been shown to be located in both atherosclerotic and nonatherosclerotic arterial intima [22][23][24][25][26] and to be associated with extracellular matrix structures and lipid droplets. 24 Interestingly, lipolysis of LDL by bee venom PLA 2 reduces the size of the LDL particles in the absence of glycosaminoglycans (GAGs) 17,20,27 but ...

“…Because the arterial intima has been shown to contain snpPLA 2 , [22][23][24][25][26] and both LDL-like particles and lipid droplets 10,43 isolated from atherosclerotic lesions show signs of phospholipid hydrolysis, we suggest that the present results can be extrapolated to the actual events in the arterial intima. snpPLA 2 is found in the intimas of even early atherosclerotic lesions 24 -26 and is occasionally found in nonatherosclerotic intimas containing considerable macrophage infiltration.…”

Section: Discussionmentioning

confidence: 77%

“…Recently, type II secretory nonpancreatic phospholipase A 2 (snpPLA 2 ), which is capable of lipolyzing LDL, 21 has been shown to be located in both atherosclerotic and nonatherosclerotic arterial intima [22][23][24][25][26] and to be associated with extracellular matrix structures and lipid droplets. 24 Interestingly, lipolysis of LDL by bee venom PLA 2 reduces the size of the LDL particles in the absence of glycosaminoglycans (GAGs) 17,20,27 but increases their size in the presence of heparin-GAG.…”

Section: See P 884mentioning

confidence: 99%

Lipolysis of LDL by Human Secretory Phospholipase A ₂ Induces Particle Fusion and Enhances the Retention of LDL to Human Aortic Proteoglycans

¹

,

²

,

³

et al. 2001

View full text Add to dashboard Cite

Abstract-The first morphological sign of atherogenesis is the accumulation of extracellular lipid droplets in the proteoglycan-rich subendothelial layer of the arterial intima. Secretory nonpancreatic phospholipase A 2 (snpPLA 2 ), an enzyme capable of lipolyzing LDL particles, is found in the arterial extracellular matrix and in contact with the extracellular lipid droplets. We have recently shown that in the presence of heparin, lipolysis of LDL with bee venom PLA 2 induces aggregation and fusion of the particles. Here, we studied the effect of human snpPLA 2 on the integrity of LDL particles and on their interaction with human aortic proteoglycans. In addition, the capacity of the proteoglycans to retain PLA 2 -lipolyzed LDL particles was tested in a microtiter well assay. We found that lipolysis of LDL induced fusion of proteoglycan-bound LDL particles, which increased their binding strength to the proteoglycans. Moreover, lipolysis of LDL with snpPLA 2 under physiological salt and albumin concentrations induced a 3-fold increase in the amount of LDL bound to proteoglycans. The results imply a role for PLA 2 in the retention and accumulation of LDL to the proteoglycan matrix in atherosclerosis. Key Words: phospholipases Ⅲ LDL Ⅲ fusion Ⅲ retention Ⅲ proteoglycans I nitiation of atherosclerosis in both humans 1 and experimental animals 2-4 is characterized by the appearance of extracellular lipid droplets in the proteoglycan (PG)-rich subendothelial layer. Experimental models have shown that similar droplets can be formed directly from LDL particles both in situ 2,5 and in vivo. 2,6 Moreover, both chemical analyses 7,8 and measurements of the size 9,10 of the extracellular lipid droplets in human arterial lesions suggest that the majority of the droplets originate from LDL particles. Because native LDL particles do not fuse into such lipid droplets, the LDL particles must undergo modification in the arterial intima. Indeed, the lipid droplets isolated from the arterial intima have features suggesting that they may have been derived from plasma LDL by extensive modification (reviewed by Öörni et al 11 ). Modification of LDL in vitro by proteolytic enzymes, 12-14 by oxidative compounds, 15 or by lipolytic enzymes such as sphingomyelinase, 13,15-17 phospholipase C, 18,19 or phospholipase A 2 (PLA 2 ) 17,20 has been shown to induce aggregation, fusion, or both aggregation and fusion of the particles. See p 884Phospholipase A 2 s are enzymes that catalyze the hydrolysis of the sn-2 fatty acyl ester bond in phospholipids, yielding a free fatty acid and a lysophospholipid. Recently, type II secretory nonpancreatic phospholipase A 2 (snpPLA 2 ), which is capable of lipolyzing LDL, 21 has been shown to be located in both atherosclerotic and nonatherosclerotic arterial intima [22][23][24][25][26] and to be associated with extracellular matrix structures and lipid droplets. 24 Interestingly, lipolysis of LDL by bee venom PLA 2 reduces the size of the LDL particles in the absence of glycosaminoglycans (GAGs) 17,20,27 but ...

“…Administration of heparin to humans results in a marked increase in plasma PLA 2 activity and immunoreactive group IIA sPLA 2 (65), suggesting that it is present in the vessel wall under physiologic conditions. Cytokines up-regulate VSMC expression of group IIA sPLA 2 in vitro (61) and in vivo (62), and sPLA 2 is present in markedly increased amounts within the atherosclerotic plaque (63,64,66). Transgenic overexpression of sPLA 2 in mice results in increased atherosclerosis (67).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

et al. 2000

Journal of Biological Chemistry

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Plasma levels of high density lipoprotein (HDL) cholesterol and its major protein component apolipoprotein (apo) A-I are significantly reduced in both acute and chronic inflammatory conditions, but the basis for this phenomenon is not well understood. We hypothesized that secretory phospholipase A 2 (sPLA 2 ), an acute phase protein that has been found in association with HDL, promotes HDL catabolism. A series of HDL metabolic studies were performed in transgenic mice that specifically overexpress human sPLA 2 but have no evidence of local or systemic inflammation. We found that HDL isolated from these mice have a significantly lower phospholipid and cholesteryl ester and significantly greater triglyceride content. transgenic mice was significantly enhanced compared with control mice. In summary, these data demonstrate that overexpression of sPLA 2 alone in the absence of inflammation causes profound alterations of HDL metabolism in vivo and are consistent with the hypothesis that sPLA 2 may promote HDL catabolism in acute and chronic inflammatory conditions. Plasma concentrations of high density lipoprotein (HDL) 1 cholesterol and its major apoprotein apoA-I are inversely associated with atherosclerotic cardiovascular disease (1, 2). The factors responsible for the substantial variation in HDL cholesterol and apoA-I levels in humans remain incompletely understood. Metabolic studies of HDL and apoA-I in humans have established that variation in their levels is due in substantial part to variation in the rate of apoA-I catabolism (3-7). Although the determinants of apoA-I catabolism have not been fully elucidated, the size and lipid composition of HDL have been recognized to substantially influence the catabolic rate of apoA-I (8, 9).One clinical setting that is invariably associated with reduced HDL cholesterol and apoA-I levels is systemic inflammation. Acute inflammatory states such as sepsis are associated with profoundly reduced HDL cholesterol levels (10). Furthermore, chronic inflammatory states such as rheumatoid arthritis and systemic lupus are also associated with reduced levels of HDL cholesterol (11-18), as well as with increased risk of cardiovascular disease (19,20). One of the major factors thought to be implicated in the reduced levels of HDL cholesterol during inflammation is the serum amyloid A (SAA) protein, which increases markedly during acute infection and inflammation and is also elevated in chronic inflammatory states (10,21,22). However, expression of SAA has never been directly demonstrated to alter HDL metabolism in vivo in the absence of systemic inflammation. We recently demonstrated that marked overexpression of human SAA alone in the absence of a generalized acute phase response had no effect on HDL cholesterol and apoA-I levels in human apoA-I transgenic mice (23). This observation raised the question as to whether other factors associated with systemic inflammation may modulate HDL metabolism.Group IIA secretory phospholipase A 2 (sPLA 2 ) is an acute phase protein and plasma leve...

“…Atherosclerosis and group IIA secretory PLA 2 (inflammatory PLA 2 )-Group IIA phospholipase A 2 (secretory PLA 2 also known as inflammatory PLA 2 ) has been found in human atherosclerotic lesions (15,16). sPLA 2 IIA is implicated in chronic inflammatory conditions such as arthritis and may also contribute to atherosclerosis (17), one of the risk factors for stroke.…”

Section: 24mentioning

confidence: 99%

Integration of cytokine biology and lipid metabolism in stroke

¹

,

2008

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Cytokines regulate the innate and adaptive immune responses and are pleiotropic, redundant and multifunctional. Expression of most cytokines, including TNF-α and IL-1α/ß, is very low in normal brain. Metabolism of lipids is of particular interest due to their high concentration in the brain. Inflammatory response after stroke suggests that cytokines (TNF-α, IL-1 α/ß, IL-6), affect the phospholipid metabolism and subsequent production of eicosanoids, ceramide, and ROS that may potentiate brain injury. Phosphatidylcholine and sphingomyelin are source for lipid messengers. Sphingomyelin synthase serves as a bridge between metabolism of glycerolipids and sphingolipids. TNF-α and IL-1 α/ß can induce phospholipases (A 2 , C, and D) and sphingomyelinases, and concomitantly proteolyse phosphatidylcholine and sphingomyelin synthesizing enzymes. Together, these alterations contribute to loss of phosphatidylcholine and sphingomyelin after stroke that can be attenuated by inhibiting TNF-α or IL-1 α/ß signaling. Inflammatory responses are instrumental in the formation and destabilization of atherosclerotic plaques. Secretory PLA 2 IIA is found in human atherosclerotic lesions and is implicated in initiation, progression and maturation of atherosclerosis, a risk factor for stroke. Lipoprotein-PLA 2 , part of apolipoprotein B-100 of LDL, plays a role in vascular inflammation and coronary endothelial dysfunction. Cytokine antagonism attenuated secretory PLA 2 IIA actions, suggesting cytokine-lipid integration studies will lead to new concepts contributing to bench-to-bedside transition for stroke therapy.

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