Abstract
Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator nigericin abolished the anti-inflammatory effects of metformin in NRVMs, but it had little effect on AMPK phosphorylation. Collectively, our study confirmed that metformin exerts cardioprotective effects by regulating myocardial I/R injury-induced inflammatory response, which was largely dependent on the enhancement of the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.
Highlights
Cardiovascular diseases, including acute myocardial infarction, are global leading cause of death [1, 2]
To confirm the cardioprotective effect of metformin postconditioning on myocardial I/R injury, myocardial infarction size was measured by using 1%TTC
To the best of our knowledge, this is the first study that examined the regulatory effect of metformin post-conditioning on the AMPK/NLRP3 inflammasome www.aging-us.com www.aging-us.com pathway following myocardial ischemia-reperfusion injury
Summary
Cardiovascular diseases, including acute myocardial infarction, are global leading cause of death [1, 2]. Rapid and safe restoration of blood supply to ischemic myocardium is considered the best and the most effective treatment for acute myocardial infarction [3]. Revascularization may aggravate myocardial damage, produce a second blow to the myocardium, and cause myocardial reperfusion injury after ischemia [4]. Exploring prevention measures and action mechanisms of ischemia/reperfusion (I/R) injury is of crucial research significance for improving the prognosis and survival rate of patients with cardiovascular disease. Several drugs have been shown to have a cardioprotective effect, preventing adverse effects of ischemic treatment on blood vessels [5]. Our previous research revealed that metformin postconditioning could protect against myocardial I/R injury [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
