Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia–reperfusion Injury in Rodents

• Type of Material: Article
• Authors: Yao Lu, Stanford University; Honit Piplani, Stanford University; Stacy McAllister, Emory University; Carl M. Hurt, Stanford University; Eric R. Gross, Stanford University
• Language: English
• Date: 2016-12
• Publisher: Lippincott, Williams & Wilkins: No Hybrid Open Access
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: (C) 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1097/ALN.0000000000001377
• Title of Journal or Parent Work: Anesthesiology
• ISSN: 0003-3022
• Volume: 125
• Issue: 6
• Start Page: 1171
• End Page: 1180
• Grant/Funding Information: This work is supported by Stanford University Department of Anesthesiology, Perioperative and Pain Management, Stanford, California, USA (ERG), National Institutes of Health, National Institute of General Medicine T32 training award GM089626 (SLM) and National Heart Lung and Blood Institute HL109212 (ERG), USA
• Keywords: immunofluorescence; rat; ischemia-reperfusion injury; cross-talk; qPCR; pain signaling; cardiac myocytes; cellular pathway; adult rat; transcient receptor potential ankyrin 1; hypoxia-reoxygenation; TRPA1; western blot
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

Background Recent evidence suggests cross-talk exists between cellular pathways important for pain signaling and ischemia-reperfusion injury. Here we address whether the transient receptor potential ankyrin 1 (TRPA1) channel, important in pain signaling, is present in cardiac myocytes and regulates cardiac ischemia-reperfusion injury. Methods For biochemical analysis of TRPA1, techniques including qPCR, western blot, and immunofluorescence were used. To determine how TRPA1 mediates cellular injury, we used an in vivo model of rat cardiac ischemia-reperfusion injury and adult rat isolated cardiac myocytes subjected to hypoxia-reoxygenation. Results Our biochemical analysis indicates TRPA1 is within the cardiac myocytes. Further, using a rat in vivo model of cardiac injury, the TRPA1 activators ASP7663 and optovin reduce myocardial injury (45±5%*, 44±8%*, respectively, versus control 66±6% infarct size/area at risk, n=6/group, mean±SD, *P<0.001). TRPA1 inhibition also blocked the infarct size sparing effects of morphine. In isolated cardiac myocytes, the TRPA1 activators ASP7663 and optovin reduce cardiac myocyte cell death when given during reoxygenation (20±3%*, 22±4%*, versus 36±3%, % of dead cells per field, n=6/group, mean±SD, *P<0.05). For a rat in vivo model of cardiac injury, the infarct size sparing effect of TRPA1 activators also occurs during reperfusion. Conclusions Our data suggests that TRPA1 is present within the cardiac myocytes and is important in regulating myocardial reperfusion injury. The presence of TRPA1 within the cardiac myocytes may potentially explain why certain pain relievers that can block TRPA1 activation, such as cyclooxygenase-2 (COX-2) inhibitors or some non-steroidal anti-inflammatory drugs (NSAIDs), could be associated with cardiovascular risk.