Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition

Ghesquiere, Stijn; Gijbels, Marion J.J.; Anthonsen, Marit W.; Gorp, Patrick J. van; Made, Ingeborg van der; Johansen, Berit; Hofker, Marten H.; Winther, Menno P.J. de

doi:10.1194/jlr.m400253-jlr200

Cited by 76 publications

(61 citation statements)

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“…In a model in which sPLA 2 was overexpressed in macrophages, it was shown that lesion size increased but interestingly, collagen accumulation was also greater, suggesting that sPLA 2 might exacerbate lesion formation but lead to a more stable lesion, i.e. one not prone to rupture (63). These findings deserve further attention.…”

Section: Discussionmentioning

confidence: 88%

“…In a transgenic mouse model, sPLA 2 led to a decrease in the levels of HDL (61,62), possibly due to the reported increase in cholesteryl ester uptake via the scavenger receptor BI by sPLA 2 -modified HDL (61). Transgenic mice overexpressing sPLA 2 either globally or in a macrophage-specific manner developed atherosclerotic lesions (63)(64)(65)(66). In a model in which sPLA 2 was overexpressed in macrophages, it was shown that lesion size increased but interestingly, collagen accumulation was also greater, suggesting that sPLA 2 might exacerbate lesion formation but lead to a more stable lesion, i.e.…”

Section: Discussionmentioning

confidence: 99%

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Secretory Phospholipase A2, Group IIA Is a Novel Serum Amyloid A Target Gene

Sullivan

Seidl

Rich

et al. 2010

Journal of Biological Chemistry

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Atherosclerosis is a multifactorial vascular disease characterized by formation of inflammatory lesions. Elevated circulating acute phase proteins indicate disease risk. Serum amyloid A (SAA) is one such marker but its function remains unclear. To determine the role of SAA on aortic smooth muscle cell gene expression, a preliminary screen of a number of genes was performed and a strong up-regulation of expression of secretory phospholipase A 2 , group IIA (sPLA 2 ) was identified. The SAAinduced increase in sPLA 2 was validated by real time PCR, Western blot analysis, and enzyme activity assays. Demonstrating that SAA increased expression of sPLA 2 heteronuclear RNA and that inhibiting transcription eliminated the effect of SAA on sPLA 2 mRNA suggested that the increase was transcriptional. Transient transfections and electrophoretic mobility shift assays identified CAAT enhancer-binding protein (C/EBP) and nuclear factor B (NFB) as key regulatory sites mediating the induction of sPLA 2 . Moreover, SAA activated the inhibitor of NF-B kinase (IKK) in cultured smooth muscle cells. Previous reports showed that interleukin (IL)-1␤ up-regulates Pla2g2a gene transcription via C/EBP␤ and NFB. Interestingly, SAA activated smooth muscle cell IL-1␤ mRNA expression, however, blocking IL-1 receptors had no effect on SAA-mediated activation of sPLA 2 expression. Thus, the observed changes in sPLA 2 expression were not secondary to SAA-induced IL-1 receptor activation. The association of SAA with high density lipoprotein abrogated the SAA-induced increase in sPLA 2 expression. These data suggest that during atherogenesis, SAA can amplify the involvement of smooth muscle cells in vascular inflammation and that this can lead to deposition of sPLA 2 and subsequent local changes in lipid homeostasis.Elevated circulating acute phase proteins correlate with an increased risk for atherosclerosis (1-4). One such disease indicator is serum amyloid A (SAA) 2 (5). The SAA protein family consists of 12-14-kDa constitutive (SAA 4 ) and acute phase (SAA 1 , SAA 2 , and SAA 3 ) isoforms. During inflammation, there are large changes in liver-derived plasma levels of the acute phase isoforms, SAA 1 and SAA 2 (6, 7). The other acute phase isoform, SAA 3 , is extrahepatically inducible (8), and although the locus equivalent to SAA 3 was previously believed to be a pseudogene in humans, Larson and co-workers (9) demonstrated its expression by mammary gland epithelial cells. Proinflammatory stimuli induce SAA expression in liver; optimal expression is achieved with a combination of interleukin (IL)-1 and IL-6 (10, 11). Extrahepatic synthesis of SAA by synovial fibroblasts, macrophages, adipocytes, and smooth muscle cells has been documented (12-15). SAA is also expressed in atherosclerotic lesions (13,16,17). Although several roles have been suggested, the functions of SAA remain uncertain (7). Our laboratory demonstrated that in response to IL-1␣, cultured aortic smooth muscle cells synthesize SAA (18) leading to the hypothesis that during ather...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Secretory Phospholipase A2, Group IIA Is a Novel Serum Amyloid A Target Gene

Sullivan

Seidl

Rich

et al. 2010

Journal of Biological Chemistry

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“…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. sPLA 2 IIA is a pro-atherogenic factor and it has been suggested that this enzyme regulates collagen deposition in the plaque and fibrotic cap development (18). sPLA 2 is one of the enzymes responsible for the release of lyso-PC via its catalytic action and these two play a crucial role in the development of atherosclerosis (19).…”

Section: 24mentioning

confidence: 99%

Integration of cytokine biology and lipid metabolism in stroke

Adibhatla

Dempsy²,

Hatcher³

2008

Front Biosci

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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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“…The sPLA 2 -II-modified lipoproteins are more susceptible to further enzymatic and oxidative modifications and to uptake by macrophages. 5,6) Thus, sPLA 2 -II plays a critical role in the formation of atherosclerotic lesions. In contrast, roles of cPLA 2 s in atherogenesis are not yet completely elucidated.…”

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confidence: 99%