Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex

Decay-accelerating factor (DAF; CD55) is a membrane protein that regulates complement pathway activity at the level of C3. To test the hypothesis that DAF plays an essential role in limiting complement activation in the arterial wall and protecting from atherosclerosis, we crossed DAF gene targeted mice (daf-1 ؊/؊ ) with low-density lipoprotein-receptor deficient mice (Ldlr ؊/؊ ). Daf-1 ؊/؊ Ldlr ؊/؊ mice had more extensive en face Sudan IV staining of the thoracoabdominal aorta than Ldlr ؊/؊ mice, both following a 12-week period of low-fat diet or a high-fat diet. Aortic root lesions in daf-1 ؊/؊ Ldlr ؊/؊ mice on a low-fat diet showed increased size and complexity. DAF deficiency increased deposition of C3d and C5b-9 , indicating the importance of DAF for downstream complement regulation in the arterial wall. The acceleration of lesion development in the absence of DAF provides confirmation of the proinflammatory and proatherosclerotic potential of complement activation in the Ldlr ؊/؊ mouse model. Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement.

“…21,40,41 In this article, we show that DAF also plays a role in the regulation of atherosclerosis in the Ldlr Ϫ/Ϫ model. All mice in the study were female.…”

mentioning

confidence: 62%

Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Leung

Yun

Botto

et al. 2009

“…35,37 Cytotoxicity Assay Hep3B cells were used because this cell line has been demonstrated to highly express human CD59. 38 We followed the same protocol as described previously 38,39 to culture the cells and to perform complement-mediated cytotoxicity assay.…”

Section: Determination Of Mac Deposition In Liver Tissuementioning

confidence: 99%

“…In addition to its anti-MAC role, CD59 has a complement-independent function in regulating activity of NK, B, and T cells, 37,40,41 which may also contribute to hepatic IRI. To define the underlying mechanism by which the deficiency of CD59 accelerates the IRI, we generated mCd59ab Ϫ/Ϫ /mC3 Ϫ/Ϫ mice by crossing mC3 C3-deficient mice (mC3 Ϫ/Ϫ ) with mCd59ab Ϫ/Ϫ mice.…”

Section: Accelerated Iri In Cd59-deficient Mice Is Complement Dependentmentioning

confidence: 99%

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

Zhang

Xing

et al. 2011

Self Cite

Hepatic ischemia-reperfusion injury (IRI) is a major factor influencing graft outcome in liver transplantation, but its mechanism is not well defined. Although complement, including the membrane attack complex (MAC), a terminal product of complement activation, is thought to be involved in the multiple reactions subsequent to the ischemia-reperfusion (IR) process, the role of MAC in the pathogenesis of hepatic IRI requires further investigation. We used a warm ischemia-reperfusion injury model in mice and a syngeneic orthotopic liver transplantation model in rats to define the role of complement, including MAC, in hepatic IR. CD59-deficient mice had more severe liver dysfunction, evidenced by increased aspartate aminotransferase levels and increased injury of liver parenchymal and nonparenchymal cells than did CD59-sufficient mice during warm hepatic IR. Furthermore, complement depletion in CD59-deficient mice by pretreatment with cobra venom factor (CVF) or the genetic introduction of C3 deficiency partially protected against development of the severe liver dysfunction that occurred in CD59-deficient mice. Severity of liver dysfunction correlated with MAC deposition, apoptotic cells, and increased inflammatory mediators such as tumor necrosis factor ␣. Liver transplantation is a routine and powerful approach for treatment of patients with acute or chronic liver failure of various causes. 1 Nevertheless, hepatic ischemia-reperfusion (IR) remains a major deleterious factor influencing graft outcome in organ transplantation. The incidence of primary graft failure (5% to 15%) and initial poor function (10% to 25%) is strongly dependent on the extent of ischemia-reperfusion injury (IRI). 2-4 IRI also initiates later graft failure by triggering irreversible intrahepatic biliary tract injury (ischemic-type biliary lesion) or by promoting rejection through activation of innate immunity. 5 At present, because of the shortage of organs for transplantation, the donor pool has been expanded by utilization of marginal organs from old donors or non-heart-beating donors, as well as grafts with prolonged cold storage, and even allografts donated after cardiac death. It is conceivable that grafts from such donors could cause severe liver injury, because they have usually experienced a long ischemia time. To improve the outcome of liver transplantation, therefore, it is imperative to better understand the mechanisms involved in IRI and to design novel therapeutic strategies for prevention of IRI.Ischemia-reperfusion injury is characterized by the presence of activated polymorphonuclear leukocytes, oxygen radical formation, 6 and cytokine release. 7,8 The process that temporarily blocks blood supply followed by blood reperfusion to the living donor after the transplantation causes attraction, activation, adhesion, and migration of neutrophils at the site of donor organ, thereby

“…Protectin has a role in prevention of vascular inflammation as indicated by studies on atherosclerosis-prone ApoE Ϫ/Ϫ mice, in which the protectindeficient mice showed signs of accelerated atherosclerosis. 36 In our previous study, we have seen lipid accumulation in the IA wall in same areas with intensive C5b-9 accumulation. 10 Thus, protectin may play a critical role in the IA wall homeostasis.…”

Section: Discussionmentioning

confidence: 62%

Lack of Complement Inhibitors in the Outer Intracranial Artery Aneurysm Wall Associates with Complement Terminal Pathway Activation

Tulamo

Frösén

Paetau

et al. 2010

Inflammation and activation of the complement system predispose to intracranial artery aneurysm (IA) rupture. Because disturbances in complement regulation may lead to increased susceptibility to complement activation and inflammation, we looked for evidence for dysregulation of the complement system in 26 unruptured and 26 ruptured IAs resected intraoperatively. Immunohistochemical and immunofluorescence results of parallel IA sections showed that deposition of the complement activation end-product C5b-9 was lacking from the luminal part of the IA wall that contained complement inhibitors factor H, C4b binding protein, and protectin as well as glycosaminoglycans. In contrast, the outer, less cellular part of the IA wall lacked protectin and had enabled full complement activation and C5b-9 formation. Decay accelerating factor and membrane cofactor protein had less evident roles in complement regulation. The Factor H Y402H variant, studied in 97 IA patients, was seen as often in aneurysm patients with or without aneurysm rupture as in the control population. The regulatory capacity of the complement system thus appears disturbed in the outer part of the IA wall, allowing full proinflammatory complement activation to occur before aneurysm rupture. Insufficient complement control might be due to matrix remodeling and cell loss by mechanical hemodynamics and/or inflammatory stress. Apparently, disturbed complement regulation leads to an increased susceptibility to complement activation , inflammation , and tissue damage in the IA wall. (Am J Pathol