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Major Contribution of the 3/6/7 Class of TRPC Channels to Myocardial Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

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Major Contribution of the 3/6/7 Class of TRPC Channels to Myocardial Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries Xiju Hea,b,c,1, Shoutian Lia,b,1, Benju Liua,b, Sebastian Susperreguyd, Karina Formosod, Jinghong Yaoe, Jinsong Kangf, Anbing Shig, Lutz Birnbaumerd,h,2, and Yanhong Liaoa,b,i,2 aDepartment of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; bInstitute of Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; cDepartment of Anatomy, Hubei University of Medicine, Shiyan, 442000, China; dInstitute of Biomedical Research (BIOMED), Catholic University of Argentina, Buenos Aires C1107AFF, Argentina; eDepartment of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; fDepartment of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; gDepartment of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; hNeurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; and iKey Laboratory of Neurological Diseases of Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China Contributed by Lutz Birnbaumer, February 24, 2017 (sent for review December 28, 2016; reviewed by Thomas Gudermann and Eric N. Olson) The injury phase after myocardial infarcts occurs during reperfusion of the mitochondrial permeability transition pore (mPTP) (2). Im- and is a consequence of calcium release from internal stores mediately after mPTP activation, mitochondria swell and release combined with calcium entry, leading to cell death by apoptopic apoptogenic and necrogenic factors, which activate caspase-dependent and necrotic processes. The mechanism(s) by which calcium enters and -independent cell death. Experimental animal studies have shown cells has(ve) not been identified. Here, we identify canonical that pharmacologically inhibiting intracellular and mitochondrial transient receptor potential channels (TRPC) 3 and 6 as the cation calcium overload at the onset of myocardial reperfusion can reduce channels through which most of the damaging calcium enters myocardial IS by 40–50% (3). However, clinical studies investigating cells to trigger their death, and we describe mechanisms activated this therapeutic approach have been disappointing thus far (4, 5), during the injury phase. Working in vitro with H9c2 cardiomyoblasts and pharmacologic intervention awaits the discovery of new drugs. + subjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), and Given that mitochondrial Ca2 overload is a leading cause of + analyzing changes occurring in areas-at-risk (AARs) of murine hearts myocardial damage in I/R injury, reducing Ca2 entry and cutting + subjected to a 30-min ischemia followed by 24-h reperfusion (I/R) off the source of Ca2 overload may prove an effective approach. + protocol, we found: (i) that blocking TRPC with SKF96365 significantly Ca2 handling by cells is orchestrated by a set of proteins, in- ameliorated damage induced by H/R, including development of the cluding the L-type calcium channel, sarco/endoplasmic reticu- + mitochondrial permeability transition and proapoptotic changes in lum Ca2 -ATPase (SERCA pump), ryanodine receptor (RyR), + Bcl2/BAX ratios; and (ii) that AAR tissues had increased TUNEL cells, sodium/calcium exchanger (NCX), and the mitochondrial calcium + augmented Bcl2/BAX ratios, and increased p(S240)NFATc3, p(S473) uniporter (MCU). Although attenuation of Ca2 overload by AKT, p(S9)GSK3β, and TRPC3 and -6 proteins, consistent with activa- targeting these proteins has provided cardioprotection in some tion of a positive-feedback loop in which calcium entering through settings of I/R (6, 7), clinical trials were limited by variables such as + TRPCs activates calcineurin-mediated NFATc3-directed transcription of the effects of chronic inhibition of Ca2 and the handling and + TRPC genes, leading to more Ca2 entry. All these changes were timing of administration, calling for a better understanding of the + markedly reduced in mice lacking TRPC3, -6, and -7. The changes regulatory mechanisms that govern Ca2 handling by the heart. caused by I/R in AAR tissues were matched by those seen after H/R in cardiomyoblasts in all aspects except for p-AKT and p-GSK3β, Significance which were decreased after H/R in cardiomyoblasts instead of in- creased. TRPC should be promising targets for pharmacologic inter- Calcium overload has been recognized as a critical cause of the vention after cardiac infarcts. injury tissues suffer after periods of ischemia. The ports that determine calcium entry into tissues subjected to transient apoptosis | necrosis | calcium overload | calcineurin | AKT hypoxia have not been identified. Here we identify two members of the transient potential receptor channel (TRPC) yocardial ischemia/reperfusion (I/R) injury is a major family of nonselective cation channels that allow passage of Mcause of morbidity and mortality in several important calcium, TRPC3 and TRPC6, as major factors causing calcium clinical scenarios, including acute myocardial infarction, cardiac entry in the heart, which is responsible for ischemia/reperfu- arrest, percutaneous coronary artery intervention, and cardiac sion (I/R) injury. Blocking TRPC activity or the genetic ablation surgery. An abiding focus on time to reperfusion, i.e., when flow of TRPCs markedly protected cardiac tissue and cells from I/R through the infarct-affected artery is reestablished either sponta- injury. TRPC3 and TRPC6 are promising therapeutic targets. neously or in response to therapeutic interventions, has proven critical for decreasing myocardial infarct size (IS) and preserving Author contributions: X.H., S.L., L.B., and Y.L. designed research; X.H., S.L., B.L., S.S., K.F., J.Y., systolic function. This event, which restores oxygen and nutrients to J.K., A.S., and Y.L. performed research; A.S. and L.B. contributed new reagents/analytic tools; X.H., S.L., B.L., S.S., J.Y., J.K., A.S., L.B., and Y.L. analyzed data; and X.H., S.L., K.F., L.B., and the injured tissues, initiates a complex set of responses, globally Y.L. wrote the paper. referred to as “I/R injury,” whichleadtocelldeathprecededby 2+ Reviewers: T.G., Ludwig Maximilian University of Munich; and E.N.O., University of Texas inflammation, production of oxygen radicals, Ca overload, and Southwestern Medical Center. activation of mitochondrial apoptosis and necrosis (1). Myocardial The authors declare no conflict of interest. 2+ Ca overload induced by I/R is a major element of myocardial 1X.H. and S.L. contributed equally to this work. 2+ dysfunction in heart failure. Mitochondrial Ca overload also can 2To whom correspondence may be addressed. Email: [email protected] or Birnbau1@ occur in cardiomyocytes as a consequence of ischemic stress during gmail.com. 2+ which aberrant intracellular Ca is taken up by mitochondria. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 2+ During I/R, Ca accumulated in mitochondria leads to the activation 1073/pnas.1621384114/-/DCSupplemental. E4582–E4591 | PNAS | Published online May 19, 2017 www.pnas.org/cgi/doi/10.1073/pnas.1621384114 Downloaded by guest on September 24, 2021 Store-operated Ca entry (SOCE), also known as “capacitative not affected by the disruption of the genes encoding TRPC3, -6, PNAS PLUS + calcium entry,” is a major mechanism of Ca2 entry existing in all and -7 as seen in 35-cycle RT-PCR tests (Fig. S2). cells, excitable and nonexcitable (8), which coexists with voltage-gated + Ca2 channels in neurons, skeletal muscle cells, and cardiomyocytes SKF96365 Protects Against Changes Induced by H/R in the in Vitro (9–12). Despite evidence that SOCE exists in cardiomyocytes, its H9c2 Myoblast Model of I/R Injury. The mitochondrial permeabil- + acceptance as a contributor to cardiomyocyte Ca2 homeostasis ity transition (mPT), which results from the assembly of the remains limited. Stromal interaction molecule 1 (STIM1) is now mPTP and the collapse of the mitochondrial membrane potential widely recognized as the molecular sensor of endoplasmic and (ψm), is one of the hallmarks of H/R injury. The presence of an + sarcoplasmic reticulum Ca2 and the trigger of SOCE. Orai1 (13– assembled mPTP can be visualized in H9c2 myoblasts subjected 15) and canonical transient receptor potential channel (TRPC) to 9-h/6-h H/R by the change in fluorescence of the tetrae- proteins (16), including TRPC1 (17–19), TRPC4 (20, 21), and thylbenzimidazolylcarbocyanine iodide (JC-1) reporter dye from TRPC5 (22), have also been shown to play important roles in red (JC-1 aggregated on the surface of polarized mitochondria) to mediating SOCE, whereas TRPC3, TRPC6, and TRPC7 have green (JC-1 distributed as monomers in the cell). As shown in Fig. been proposed, but not conclusively been proven to participate in 2A, normoxic H9c2 cells stain red, whereas cells subjected to H/R + the SOCE phenomenon, i.e., thapsigargin-evoked Ca2 entry (23– stain green. The addition of SKF96365 during the H/R protocol 25). TRPC proteins originate in seven genes coding for channel inhibited the development of the mPT in a dose-dependent proteins (TRPC1–TRPC7) that are grouped into subfamilies by manner, suggesting
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