A role of TRPC3/6 in Myocardial Ischemia and Reperfusion (I/R) Injury

LIAO, YANHONG; LIU, BENJU; LUTZ BIRNBAUMER; FORMOSO, KARINA; HE, XIJU; SUSPERREGUY, SEBASTIAN; LI, SHOUTIAN

Simposio; The 42nd Symposium on Hormones and Cell Regulation Ion Channels in Hormonal Homeostasis: Transient Receptor Potential Channels and Calcium Signaling; 2017

European Society of Endocrinology

Calciumoverload plays an important role in myocardiac ischemia and reperfusion injury.But the detailed mechanism by which excessive calcium ions enters cardiacmyocytes has not been fully elucidated.  Herewe identify TRPC3 and TRPC6 as primary channels via which excessive calciumions are accumulated in the cytosol of cardiomyocytes, leading to cell death inIR process. In In vivo experimentswith TRPC3/6/7 KO mice and WT counterparts, animals were subjected to a 30-min/24-h I/R protocol. We observed: (1)the infarct size (IS) in TRPC3/6/7 KO mice is clearly smaller than in WT age-matchedcontrols (Evans/TTC staining); (2) cardiac functionality of TRPC3/6/7 KO miceis better than that in WT controls (echocardiograph recording); (3) myocardialfibers and mitochondaria are less disrupted in AAR tissue of TRPC3/6/7 KO mice,compared to that in WT controls (LM, EM); (4) apopotic cells are less in AAR tissue of TRPC3/6/7 KO mice, compared toWT contros (TUNEL staining). In in vitro experiments,H9c2 cardiomyoblasts were subjected to a 9-h/6-h H/R protocol. We observedthat: (1) H/R increases mitochondria?s permeability transition which is attenuatedby the non-Orai inhibiting, 5 uM TRPC pan-blocker SKF96365; (2) H/R enhancesproapoptotic the process (Bcl2/Bax ratio decrease); (3) H/R decreases p-NFAT(S240) and increases the expression of TRPC3, TRPC6 and Bax. We noticed adiscrepancy in the expressions of p-AKT and p-GSK3b between I/R-treated AARtissue (increase), and in H/R-treated H9c2 myoblast cells (decrease). We conclude that thepositive-feedback loop which elevates cytosolic calcium via TRPC3 and TRPC6 inI/R activates calcineurin-mediated NFATc3 directed TRPC3 and 6 transcription,yielding more TRPC3 and 6, leading to pathological calcium overload, andtriggering I/R injuries