Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice

Harhausen, Denise; Khojasteh, Uldus; Stahel, Philip F.; Morgan, B. Paul; Nietfeld, Wilfried; Dirnagl, Ulrich; Trendelenburg, George

doi:10.1186/1742-2094-7-15

Cited by 51 publications

(43 citation statements)

References 57 publications

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“…Although the protective role of CD59 in hepatic IRI has not been defined previously, the protective role of CD59 in renal IRI 26 and in cerebral ischemia 48 has been elucidated by utilization of deficiency of the mCd59a, a primary murine. 27,49,50 These results, together with the fact that CD59 is universally expressed in almost of all cells in a variety of organs, indicate that CD59 may protect against the IRI in organs other than liver, kidney, and brain.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Xing

et al. 2011

The American Journal of Pathology

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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

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Section: Discussionmentioning

confidence: 99%

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

Zhang

Xing

et al. 2011

The American Journal of Pathology

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“…Despite the absence of differences in the stroke volume, adult male Sirt2 − / − mice showed less neurological impairment (measured by the mNSS) 24 and 48 hours after induction of cerebral ischemia for 45 minutes ( Figure 3). We could not detect a significant difference between the two groups 24 hours after MCAO using the Bederson Score (P = 0.3661, median 2 in both groups).…”

Section: Sirt2-deficieny Preserves Neurological Function After Cerebrmentioning

confidence: 95%

Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice

Krey

Lühder

Kusch

et al. 2015

J Cereb Blood Flow Metab

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Sirtuin-2 (Sirt2) is a member of the NAD(+)-dependent protein deacetylase family. Various members of the sirtuin class have been found to be involved in processes related to longevity, regulation of inflammation, and neuroprotection. Induction of Sirt2 mRNA was found in the whole hemisphere after experimental stroke in a recent screening approach. Moreover, Sirt2 protein is highly expressed in myelin-rich brain regions after stroke. To examine the effects of Sirt2 on ischemic stroke, we induced transient focal cerebral ischemia in adult male Sirt2-knockout and wild-type mice. Two stroke models with different occlusion times were applied: a severe ischemia (45 minutes of middle cerebral artery occlusion (MCAO)) and a mild one (15 minutes of MCAO), which was used to focus on subcortical infarcts. Neurological deficit was determined at 48 hours after 45 minutes of MCAO, and up to 7 days after induction of 15 minutes of cerebral ischemia. In contrast to recent data on Sirt1, Sirt2(-/-) mice showed less neurological deficits in both models of experimental stroke, with the strongest manifestation after 48 hours of reperfusion. However, we did not observe a significant difference of stroke volumes or inflammatory cell count between Sirt2-deficient and wild-type mice. Thus we postulate that Sirt2 mediates myelin-dependent neuronal dysfunction during the early phase after ischemic stroke.

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“…Neurologic deficits were determined according to a 0-5 point scale of neurological score system as published [18]. 0 = no neurological dysfunction; 1 = failure to extend left forelimb fully when lifted by tail; 2 = circling to the contralateral side; 3 = falling to the left; 4 = no spontaneous walk or in a comatose state; 5 = death.…”

Section: Evaluation Of Neurological Deficitsmentioning

confidence: 99%

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity

Hu¹,

Doll²,

Sun³

et al. 2016

Aging and disease

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Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients -targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.

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Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice

Abstract: Background: The complement system is a crucial mediator of inflammation and cell lysis after cerebral ischemia. However, there is little information about the exact contribution of the membrane attack complex (MAC) and its inhibitor-protein CD59.

Cited by 51 publications

References 57 publications

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

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

Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity

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