Antithrombin is protective against myocardial ischemia and reperfusion injury

Abstract

Summary Background Antithrombin (AT) is a plasma serpin inhibitor that regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to its anticoagulant activity, AT also possesses potent antiinflammatory properties. Objectives The objective of this study is to investigate the antiinflammatory activity of wild-type AT (AT-WT) and a reactive center loop mutant of AT (AT-RCL) which is not capable of inhibiting thrombin. Methods Cardioprotective activities of AT-WT and AT-RCL were monitored in a mouse model of ischemia/reperfusion injury in which the left anterior descending coronary artery was occluded and then released. Results We demonstrate that AT markedly reduces myocardial infarct size by a mechanism that is independent of its anticoagulant activity. Thus, AT-RCL attenuated myocardial infarct size to the same extent as AT-WT in this acute injury model. Further studies revealed that AT binds to vascular heparan sulfate proteoglycans via its heparin-binding domain to exert its protective activity as evidenced by the therapeutic AT-binding pentasaccharide (fondaparinux) abrogating the cardioprotective activity of AT and a heparin-site mutant of AT exhibiting no cardioprotective property. We further demonstrate that AT up-regulates production of prostacyclin in myocardial tissues and inhibits expression of proinflammatory cytokines TNF-α and IL-6 in vivo by attenuating ischemia/reperfusion-induced JNK and NF-κB signaling pathways. Conclusions Our results suggest that both AT and the non-anticoagulant AT-RCL, through their antiinflammatory signaling effects, elicit potent cardioprotective responses. Thus, AT may have therapeutic potential for treating cardiac ischemia/reperfusion injury.

Inhibition of coagulation proteases Xa and IIa decreases ischemia–reperfusion injuries in a preclinical renal transplantation model

“…25 Herein, in vivo, we observed a decrease of TAT formation at 60 min post-reperfusion when the kidney was preserved with anticoagulants. Since a direct link between thrombin activity and pro-inflammatory response has been established in IR context, in mice 26 and rat, 27 our results further suggest that EP217609-dependent "thrombin" inhibition may limit inflammation.…”

GsMTx4-D is a cardioprotectant against myocardial infarction during ischemia and reperfusion

“…C57Bl/6J mice (4–6 months of age) were obtained from Jackson Laboratories (Bar Harbor, MN). For the ischemia experiments, mice were anesthetized with 4% isoflurane and 100% O 2 , quickly intubated and ventilated with a respirator (Harvard apparatus, Holliston, MA, USA) [29]. The amount of isoflurane was slowly reduced to 1–3%.…”

“…We continuously recorded ECGs during reperfusion [29], providing mean heart rate, PR, QRS and QT intervals for each animal. We evaluated the incidence of arrhythmias according to the criteria of Huggins et al [30] and Lujan and DiCarlo [31].…”

“…Immunoblotting was performed as previously described [29,36]. Isolated cardiomyocyte proteins were resolved by SDS-PAGE and transferred onto polyvinylidene difluoride membranes (Millipore, Bedford, MA, USA).…”

Hyperoside inhibits biofilm formation of Pseudomonas aeruginosa

“…Flavonoids are plant polyphenols present in vegetables, fruits and beverages of plant origin and are well known for their antipyretic, analgesic and anti-inflammatory physiological properties (14)(15)(16)(17)(18). Hyperoside is a type of modified flavonoid.…”