Antithrombin up-regulates AMP-activated protein kinase signalling during myocardial ischaemia/reperfusion injury

Abstract

Summary Antithrombin (AT) is a protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to heparan sulfate proteoglycans (HSPGs) on vascular cells. AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischemia and reperfusion (I/R). To determine whether the cardioprotective signaling function of AT is mediated through the AMPK pathway, we evaluated the cardioprotective activities of wild-type AT and its two derivatives, one having high affinity and the other no affinity for heparin, in an acute I/R injury model in C57BL/6J mice in which the left anterior descending coronary artery was occluded. The serpin derivatives were given 5 min before reperfusion. The results showed that AT-WT can activate AMPK in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK and in limiting infraction, but the derivative lacking affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity induced by AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. These results suggest that AT binds to HSPGs on heart tissues to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes

“…Once activated, AMPK could switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as synthesis of lipids, carbohydrates, and proteins (Hardie, 2003). In the hearts of transgenic mice overexpressing inactive AMPKα2 would not benefit from the myocardial preconditioning when subjected to I/R due to failure of regulating the activity and recruitment of sarcolemmal KATP channels (Sukhodub et al, 2007), and the cardioprotective actions of antithrombin may trigger cardiac AMPK activation, thereby inhibiting JNK inflammatory signaling pathways and modulating substrate metabolism during I/R (Ma et al, 2015). These researches illustrated that AMPK may benefit hearts subjected to I/R injury.…”

Master redox regulator Trx1 upregulates SMYD1 & modulates lysine methylation

“…A recombinant serpin, LEX032, has been shown to reduce the infarct size in a mouse ischemia/reperfusion model by inhibiting neutrophil accumulation and thus, preventing superoxide release from the neutrophils [41,42]. Another study by Ma et al showed that antithrombin, a serpin, exhibited anti-inflammatory and cardioprotection activity during ischemia/reperfusion injury by activating the AMPK signaling pathway [43]. Upregulation of these proteins in Tg-Trx1 mice during TAC suggests that new pathways, such as myofibril organization, may be regulated by Trx1 during cardiac stress and will require further studies to understand their exact mechanisms.…”

The structure-activity relationship of ginsenosides on hypoxia-reoxygenation induced apoptosis of cardiomyocytes

“…Prolonged ischemia causes a drop in ATP levels and an increase in anaerobic metabolism, which results in tissue damage/death [21,22]. Reperfusion of acute or chronic ischemic myocardium is necessary for restoring the flow of blood in order to salvage the myocardium.…”