Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria

LIFE SCIENCES

卷:235

Article

Ponnalagu, Devasena^1,2  Hussain, Ahmed Tafsirul¹  Thanawala, Rushi¹  Meka, Jahnavi¹  Bednarczyk, Piotr³  Feng, Yansheng⁴  Szewczyk, Adam⁵  GururajaRao, Shubha^1,2  Bopassa, Jean C.⁴  Khan, Mahmood^2,6  Singh, Harpreet^1,2 

[1] Drexel Univ, Coll Med, Dept Pharmacol & Physiol, Philadelphia, PA 19102 USA

[2] Ohio State Univ, Dept Physiol & Cell Biol, 460 Med Ctr Dr,420, Columbus, OH 43210 USA

[3] Warsaw Univ Life Sci SGGW, Dept Biophys, Warsaw, Poland

[4] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Integrat Physiol, San Antonio, TX 78229 USA

[5] Nencki Inst Expt Biol, Dept Biochem, Warsaw, Poland

[6] Ohio State Univ, Dept Emergency Med, Columbus, OH 43210 USA

关键词: Mitochondria;    Chloride intracellular channel proteins;    Myocardial infarction;    Cardioprotection;    Calcium retention capacity;   

DOI  :  10.1016/j.lfs.2019.116841

来源: Elsevier

【 摘 要 】

Indanyloxyacetic acid-94 (IAA-94), an intracellular chloride channel blocker, is shown to ablate cardioprotection rendered by ischemic preconditioning (IPC), N (6)-2-(4-aminophenyl) ethyladenosine or the PKC activator phorbol 12-myristate 13-acetate and cyclosporin A (CsA) in both ex-vivo and in-vivo ischemia-reperfusion (IR) injury. Thus signifying the role of the IAA-94 sensitive chloride channels in mediating cardio-protection upon IR injury. Although IAA-94 sensitive chloride currents are recorded in cardiac mitoplast, there is still a lack of understanding of the mechanism by which IAA-94 increases myocardial infarction (MI) by IR injury. Mitochondria are the key arbitrators of cell life and death pathways. Both oxidative stress and calcium overload in the mitochondria, elicit pathways resulting in the opening of mitochondrial permeability transition pore (mPTP) leading to cell death. Therefore, in this study we explored the role of IAA-94 in MI and in maintaining calcium retention capacity (CRC) of cardiac mitochondria after IR. IAA-94 inhibited the CRC of the isolated cardiac mitochondria in a concentration-dependent manner as measured spectrofluorimetrically using calcium green-5 N. Interestingly, IAA-94 did not change the mitochondrial membrane potential. Further, CsA a blocker of mPTP opening could not override the effect of IAA-94. We also showed for the first time that IAA-94 perfusion after ischemic event augments MI by reducing the CRC of mitochondria. To conclude, our results demonstrate that the mechanism of IAA-94 mediated cardio-deleterious effects is via modulating the mitochondria CRC, thereby playing a role in mPTP opening. These findings highlight new pharmacological targets, which can mediate cardioprotection from IR injury.

【 授权许可】

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