Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries

HE, XIJU; LI, SHOUTIAN; LIU, BENJU; SUSPERREGUY, SEBASTIAN; FORMOSO, KARINA; YAO, JINGHONG; KANG, JINSONG; SHI, ANBING; BIRNBAUMER, LUTZ; LIAO, YANHONG

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Año: 2017

0027-8424

">The injury phase after myocardial infarcts occurs during reperfusionand is a consequence of calcium release from internal storescombined with calcium entry, leading to cell death by apoptopicand necrotic processes. The mechanism(s) by which calcium enterscells has(ve) not been identified. Here, we identify canonicaltransient receptor potential channels (TRPC) 3 and 6 as the cationchannels through which most of the damaging calcium enterscells to trigger their death, and we describe mechanisms activatedduring the injury phase. Working in vitro with H9c2 cardiomyoblastssubjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), andanalyzing changes occurring in areas-at-risk (AARs) of murine heartssubjected to a 30-min ischemia followed by 24-h reperfusion (I/R)protocol, we found: (i) that blocking TRPC with SKF96365 significantlyameliorated damage induced by H/R, including development of themitochondrial permeability transition and proapoptotic changes inBcl2/BAX ratios; and (ii) that AAR tissues had increased TUNEL+ cells,augmented Bcl2/BAX ratios, and increased p(S240)NFATc3, p(S473)AKT, p(S9)GSK3β, and TRPC3 and -6 proteins, consistent with activation of a positive-feedback loop in which calcium entering throughTRPCs activates calcineurin-mediated NFATc3-directed transcription ofTRPC genes, leading to more Ca2+ entry. All these changes weremarkedly reduced in mice lacking TRPC3, -6, and -7. The changescaused by I/R in AAR tissues were matched by those seen afterH/R in cardiomyoblasts in all aspects except for p-AKT and p-GSK3β,which were decreased after H/R in cardiomyoblasts instead of increased. TRPC should be promising targets for pharmacologic intervention after cardiac infarcts.