Oxidized Phospholipids Alter Vascular Connexin Expression, Phosphorylation, and Heterocellular Communication

Isakson, Brant E.; Krönke, Gerhard; Kadl, Alexandra; Leitinger, Norbert; Duling, Brian R.

doi:10.1161/01.atv.0000237608.19055.53

Cited by 39 publications

(33 citation statements)

References 36 publications

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“…In unpublished studies, 0.1 mg/ml of PEIPC showed significant effects on SMC differentiation. OxPLs also potently affect connexin expression and function in endothelial cells and SMCs (37), which may have significant effects on the progression of atherosclerotic lesions by enhancing smooth muscle cell interaction with the endothelium in the fibrous plaque (38). The in vitro effects of Ox-PAPC led to connexin changes seen in atherosclerotic lesions.…”

Section: Smcsmentioning

confidence: 99%

“…However, we think it is important to point out the increasing evidence that OxPLs play a role in human atherosclerosis. These include 1) the observation that the plasma levels of OxPC CD36 correlate with platelet response to agonists (39); and 2 ) signal transduction pathways, SREBP, UPR, STAT3, and CNX 43, activated by Ox-PAPC in vitro are also activated in human lesions (11,37). Perhaps the strongest evidence comes from 3 ) the prognostic value of OxPLs on apolipoprotein B-100 particles (OxPL/apoB) measured with antibody E06.…”

Section: Evidence For a Role Of Oxpls In Human Atherosclerosismentioning

confidence: 99%

See 1 more Smart Citation

The role of oxidized phospholipids in atherosclerosis

Berliner

Leitinger

Tsimikas

2009

Journal of Lipid Research

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219

110

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There is increasing evidence that oxidized phospholipids (OxPLs) play an important role in atherosclerosis. These phospholipids accumulate in human and mouse lesions. Specific OxPLs have been identified as major regulators of many cell types present in the vessel wall. In endothelial cells, .1,000 genes are regulated. Some of these genes are pro-atherogenic and others anti-atherogenic. The anti-atherogenic effects are likely important in slowing the atherogenic process. Several receptors and signaling pathways associated with OxPL action have been identified and shown to be upregulated in human lesions. A structural model of the mechanism by which specific OxPLs serve as CD36 ligands has been identified. Specific oxidized phospholipids are also present in plasma and associated with Lp(a) particles. In humans, OxPL/apolipoprotein B has been shown to be a prognostic indicator and a separate risk factor for coronary events. CHEMISTRY OF OXIDIZED PHOSPHOLIPIDSSeveral reviews and original articles have identified the structure of bioactive oxidized phospholipids that are formed from PUFAs at the sn-2 position (1-3). The number of oxidation products from each PUFA is likely at least 50, and effects of all of these products have not been examined. For the purposes of this review, we will only include structures of several well-studied molecules (Fig. 1). Bioactive oxidized phospholipids may contain fragmentation products of PUFA, such as 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phoshorylcholine and 9-keto-10-dodecendioic acid ester of 2-lyso-phosphatidyl choline (KOdiA-PC); prostaglandins, such as 15 deoxy-delta12,14 prostaglandin J2 (PGJ2) and 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphoryl choline (PEIPC); and levuglandins. These molecules exhibit different biological activities. An important recent development is a better understanding of the initial interaction of oxidized phospholipids with cells. Receptors have been identified, including CD36, SRB1, EP2, VEGFR2, and the PAF receptor (1, 4). An interaction with TLR4 has also been suggested in some studies but not others (1, 5). A possible mechanism by which cells recognize oxidized phospholipids has been suggested involving the novel confirmation of these lipids in membranes (6). These studies demonstrated that, when present in vesicles, truncated oxidized fatty acids at the sn-2 position move from the hydrophobic interior to the aqueous exterior of the vesicle. This would allow their recognition by cell surface receptors. An earlier model of isoprostane-containing phospholipids suggests that they are highly twisted and may distort membrane areas in which they are present (7). These studies and others (8) suggest that phospholipid oxidation products can integrate into lipid membranes of cells and lipoproteins; they then can either act as ligands or may cause local membrane disruption. In addition, strong evidence has been presented for the ability of oxidized phospholipids to form protein adducts. Probably the most well characterized are th...

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Section: Smcsmentioning

confidence: 99%

Section: Evidence For a Role Of Oxpls In Human Atherosclerosismentioning

confidence: 99%

The role of oxidized phospholipids in atherosclerosis

Berliner

Leitinger

Tsimikas

2009

Journal of Lipid Research

Self Cite

219

110

View full text Add to dashboard Cite

show abstract

“…However, different connexins have been identified in a same tissue or cell. For instance, Cx40, Cx43, and Cx45 are the three major connexins found in the myocardiac cells (Carlen et al, 2000), while Cx37, Cx40, and Cx43 are specific to VSMCs (Isakson et al, 2006). In normal vascular wall, the integrity of endothelial cells is essential for the maintenance of the physiology of blood vessels.…”

Section: Discussionmentioning

confidence: 99%

Effects of Losartan and Ramipril on the connexin expression in a rabbit balloon injury model

Li¹,

Li²,

Duan³

et al. 2011

Afr. J. Pharm. Pharmacol.

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Intercellular gap junction (GJ) plays a pivotal role in the proliferation and transformation of vascular smooth muscle cells (VSMCs). This study was designed to test the hypothesis that expressions of the component proteins of gap junctions, connexins40 and 43 (Cx40 and Cx43), are up-regulated in arteries subjected to balloon injury and that this up-regulation can be suppressed by statin therapy. Transmission electron microscopy (TEM) revealed that there were abundant GJ between neointimal SMCs but fewer and smaller GJ after losartan and ramipril treatment. Reverse transcription-polymerase chain reaction and Western blot analysis showed the messenger ribonucleic acid (mRNA) and protein expressions of Cx40 and Cx43 were elevated after injury, and these elevations were suppressed by losartan and ramipril. Immunostaining showed the Cx40 and Cx43 expressions were consistently enhanced in the neointimal area after injury, which was decreased by losartan and ramipril treatment. Balloon injury causes up-regulation of Cx40 and Cx43 in neointimal SMCs. angiotensin-converting enzyme inhibitors (ACEIs) and AT 1 antagonist losartan can reduce the proliferation of SMCs, suggesting the rennin-angiotensin system (RAS) system plays an important role in the remodeling of GJ in the VSMCs under pathological conditions.

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“…In the vitro coculture model of EC and SMC, biocytin dye transfer between EC and VSMC coupling was dramatically reduced by OxPAPC. The decrease in dye transfer after OxPAPC treatment was correlated with an increase in tyrosine 265 phosphorylation of Cx43, especially at the in vitro myoendothelial junction (Isakson et al, 2006). Application of adenosine 3',5'-cyclic monophosphate sodium (pCPT) to mouse cremasteric arterioles reduces the detection of Cx43 phosphorylated at its carboxyl terminal Ser-368 at the MEJ in vivo (Straub et al, 2010).…”

Section: Gap Junction Between Endothelial Cell and Smcmentioning

confidence: 99%

Study progress of homocellular and heterocellular gap junctions in vessel wall

Hedagger;¹

2012

Afr. J. Pharm. Pharmacol.

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There were four different degrees which were related to organs, tissues, cells and molecules in the study of physiopathologic process and treatment of vessel remodeling diseases. More people concentrated on the research of one kind of cell, for example, the vascular smooth muscle cell (VSMC) or adventitial fibroblast (AF) and their effect on the vessel rebuilding. However, the human body is an organic whole, so the structural and functional contacts among vascular endothelial cell, smooth muscle cell (SMC) and AF should be paid more attention to. Books and articles on the gap junction (GJ) were collected and studied. Gap junction between and among cells of the vessel wall played a critical role in many aspects of vascular function and pathology. There was homocellular communication in intima, tunicae media and adventitia singly, and also, heterocellular communication among different cells of the vessel wall. As a result, a link network was formed among cells of the vessel wall and the vessel had integrated function in the physiological and pathological process. Hence, a summary was made about the homocellular and heterocellular gap junctions, hoping that there would be more people concentrating on the whole function of vessels.

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Oxidized Phospholipids Alter Vascular Connexin Expression, Phosphorylation, and Heterocellular Communication

Cited by 39 publications

References 36 publications

The role of oxidized phospholipids in atherosclerosis

The role of oxidized phospholipids in atherosclerosis

Effects of Losartan and Ramipril on the connexin expression in a rabbit balloon injury model

Study progress of homocellular and heterocellular gap junctions in vessel wall

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