Prolonged cardiac allograft survival in presensitized rats after a high activity Yunnan-cobra venom factor therapy

Complement-dependent antibody-mediated acute humoral rejection is the major obstacle of clinical transplantation across ABO incompatibility and human leukocyte antigen presensitization. We previously demonstrated that Yunnan-cobra venom factor (Y-CVF) cou

Prolonged cardiac xenograft survival in guinea pig-to-rat model by a highly active cobra venom factor

A highly active cobra venom factor (CVF) was isolated from the venom of Naja kaouthia by sequential column chromatography. It displays strong anticomplementary activity, and has 1515 U of anti complementary activity per mg protein. A single dose of 0.1 mg/kg CVF given i.v. to rats completely abrogated complement activity for nearly 5 days. Given 0.02 mg/kg of CVF. the complement activity of rats was reduced by more than 96.5% in 6 It. In guinea pig-to-rat heart transplant model, rats treated with a single dose of 0.05 mg/kg CVF had significantly prolonged xenograft survival (56.12 +/- 6.27 h in CVF-treated rats vs. 0.19 +/- 0.07 h in control rats, P < 0.001). (C) 2003 Elsevier Ltd. All rights reserved.

Improved suppression of circulating complement does not block acute vascular rejection of pig-to-rhesus monkey cardiac transplants

At present, acute vascular rejection (AVR) remains a primary obstacle inhibiting long-term graft survival in the pig-to-non-human primate transplant model. The present study was undertaken to determine whether repetitive injection of low dose Yunnan-cobra venom factor (Y-CVF), a potent complement inhibitor derived from the venom of Naja kaouthia can completely abrogate hemolytic complement activity and subsequently improve the results in a pig-to-rhesus monkey heterotopic heart transplant model. Nine adult rhesus monkeys received a heterotopic heart transplant from wild-type pigs and the recipients were allocated into two groups: group 1 (n = 4) received repetitive injection of low dose Y-CVF until the end of the study and group 2 (n = 5) did not receive Y-CVF. All recipients were treated with cyclosporine A (CsA), cyclophosphamide (CyP) and steroids. Repetitive Y-CVF treatment led to very dramatic fall in CH50 and serum C3 levels (CH50 < 3 units/C3 remained undetectable throughout the experiment) and successfully prevented hyperacute rejection (HAR), while three of five animals in group 2 underwent HAR. However, the continuous suppression of circulating complement did not prevent AVR and the grafts in group 1 survived from 8 to 13 days. Despite undetectable C3 in circulating blood, C3 deposition was present in these grafts. The venular thrombosis was the predominant histopathologic feature of AVR. We conclude that repetitive injection of low dose Y-CVF can be used to continuously suppress circulating complement in a very potent manner and successfully prevent HAR. However, this therapy did not inhibit complement deposition in the graft and failed to prevent AVR. These data suggest that using alternative pig donors [i.e. human decay accelerating factor (hDAF)-transgenic] in combination with the systemic use of complement inhibitors may be necessary to further control complement activation and improve survival in pig-to-non-human primate xenotransplant model.

TMVA, a novel GPIb-binding protein, significantly prevents platelet microthrombi formation and prolongs discordant cardiac xenograft survival

In xenotransplantation, donor endothelium is the first target of immunological attack. Activation of the endothelial cell by preformed natural antibodies leads to platelet binding via the interaction of the glycoprotein (GP) Ib and von Willebrand factor (vWF). TMVA is a novel GPIb-binding protein purified from the venom of Trimeresurus mucrosquamatus. In this study, the inhibitory effect of TMVA on platelet aggregation in rats and the effect on discordant guinea pig-to-rat cardiac xenograft survival were investigated. Three doses (8, 20 or 40 mug/kg) of TMVA were infused intravenously to 30 rats respectively. Platelet aggregation rate was assayed 0.5, 12, and 24 h after TMVA administration. Wister rats underwent guinea pig cardiac cervical heterotopic transplantation using single dosing of TMVA (20 mug/kg, i.v., 0.5 h before reperfusion). Additionally, levels of TXB2 and 6-keto-PGF(1alpha) within rejected graft tissues were determined by radioimmunoassay. Treatment with TMVA at a dose of 20 or 40 mug/kg resulted in complete inhibition of platelet aggregation 0.5 h after TMVA administration. Rats receiving guinea pig cardiac xenografts after TMVA therapy had significantly prolonged xenograft survival. Histologic and immunopathologic analysis of cardiac xenografts in TMVA treatment group showed no intragraft platelet microthrombi formation and fibrin deposition. Additionally, the ratio of 6-keto-PGF(1alpha) to TXB2 in TMVA treatment group was significantly higher than those in control group. We conclude that the use of this novel GPIb-binding protein was very effective in preventing platelet microthrombi formation and fibrin deposition in a guinea pig-to-rat model and resulted in prolongation of xenograft survival. The increased ratio of PGI(2)/TXA(2) in TMVA treatment group may protect xenografts from the endothelial cell activation and contribute to the prolongation of xenograft survival.

The profound effects of microcystin on cardiac antioxidant enzymes, mitochondrial function and cardiac toxicity in rat

Deaths from microcystin toxication have widely been attributed to hypovolemic shock due to hepatic interstitial hemorrhage, while some recent studies suggest that cardiogenic complication is also involved. So far, information on cardiotoxic effects of MC has been rare and the underlying mechanism is still puzzling. The present study examined toxic effects of microcystins on heart muscle of rats intravenously injected with extracted MC at two doses, 0.16LD(50) (14 mu g MC-LReq kg(-1) body weight) and 1LD(50) (87 mu g MC-LReq kg(-1) body weight). In the dead rats, both TTC staining and maximum elevations of troponin I levels confirmed myocardial infarction after MC exposure, besides a serious interstitial hemorrhage in liver. In the 1LD(50) dose group, the coincident falls in heart rate and blood pressure were related to mitochondria dysfunction in heart, while increases in creatine kinase and troponin I levels indicated cardiac cell injury. The corresponding pathological alterations were mainly characterized as loss of adherence between cardiac myocytes and swollen or ruptured mitochondria at the ultrastructural level. MC administration at a dose of 1LD(50) not only enhanced activities and up-regulated mRNA transcription levels of antioxidant enzymes, but also increased GSH content. At both doses, level of lipid peroxides increased obviously, suggesting serious oxidative stress in mitochondria. Simultaneously. complex I and III were significantly inhibited, indicating blocks in electron flow along the mitochondrial respiratory chain in heart. In conclusion, the findings of this study implicate a role for MC-induced cardiotoxicity as a potential factor that should be considered when evaluating the mechanisms of death associated with microcystin intoxication in Brazil. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

A型、D型人格影响冠心病预后的心理生理机制

Coronary heart disease （CHD）is a common cardiovascular disease in the elderly, is also a typical psychosomatic disease. Personality factors are very important in many psychological factors impacting on the prognosis of patients with CHD. The most influential personality factors to CHD are Type A and Type D personality. The previous research has shown that although Type A personality increased the prevalence of CHD, it cannot predict the development and prognosis after diagnosis. In contradict, Type D personality can predict prognosis. There is still no clinic-based or theory-based answer to the question: Why Type A personality cannot predict the outcome while Type D personality could predict the prognosis independently. The current research conducted a systematic investigation to the above question, which included one comparison study between CHD patients and control group, and four studies on reaction experiment and answered the question: why Type A personality cannot predict whereas Type D personality could effectively predict prognosis of CHD. The findings of the current research were: Type A and Type D personality influence CHD prognosis through different psychological mechanisms: both dimensions of Type D personality have direct influence on social support, whereas neither dimensions of Type A personality related to social support, directly of indirectly. Negative affection component of Type D personality significantly related to anxiety and depression, Social repression significantly related to anxiety but not depression. Both dimensions of Type A personality significantly related to anxiety but not depression. Neither under rest or diaphragmatic breathing conditions, Type A personality had no significant influence on vestibular autonomic reaction among healthy young males. Neither Type A nor Type D personality had significant influence on vestibular autonomic reaction among old CHD patients under rest condition. Type D personality predicted lower sympathetic excitation under rest condition, and lower cardiac vagal tone under diaphragmatic breathing condition among healthy young males. When actively reacted to stimuli (math calculation) under rest condition, Type A personality increased sympathetic excitation among healthy young males. When actively reacted to stimuli (math calculation) under diaphragmatic breathing condition, Type A personality increased cardiac vagal tone among the same group of subjects. When actively reacted to stimuli under neither condition, Type D personality showed no significant influence on vestibular autonomic reaction among young males. When passively reacted to stimuli under neither condition, Type A personality showed no significant influence on vestibular autonomic reaction among young males. When passively stimulated followed rest, Type D personality increased sympathetic excitation and decreased cardiac vagal tone among young males. When passively stimulated followed diaphragmatic breathing, Typed showed no significant influence on vestibular autonomic reaction among young males. The above results indicated that Type A and Type D personalities had different psychological mechanisms to the outcome of CHD treatment: neither dimensions of Type A personality had direct or indirect effects on social support; both dimensions of Type D personality had direct and indirect effects on social support. Negative affection component of Type D personality significantly related to anxiety and depression, Social repression significantly related to anxiety but not depression. Both dimensions of Type A personality significantly related to anxiety but not depression. Social support positively related to the outcome after CHD treatment. The biological mechanisms of Type A and Type B personality to CHD prognosis differed in the following ways: Type A personality increased sympathetic excitation when actively stimulated, but had no influence when passively stimulated among young male subjects. When passively stimulated after rest, Type D personality predicted high sympathetic excitation and low cardiac vagal tone among young males, but not vestibular autonomic reaction among young males. Key words: Type A personality, Type D personality, Coronary Heart Disease (CHD), Prognosis, Psychobiological Mechanisms