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Inhibition of Cyclophilin D During Acute and Chronic Myocardial Infarction in Rats: The Effect of Reperfusion
Author(s) -
ParodiRullán Rebecca Maria,
SotoPrado Jadira,
VegaLugo Jesús,
ChapaDubocq Xavier,
Javadov Sabzali
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1080.11
Subject(s) - mptp , mitochondrial permeability transition pore , cardioprotection , myocardial infarction , medicine , reperfusion injury , ischemia , mitochondrion , pharmacology , cardiology , heart failure , chemistry , programmed cell death , apoptosis , biochemistry , parkinson's disease , disease
Background Mitochondrial permeability transition pore (mPTP) opening plays a critical role in pathogenesis of myocardial infarction (MI) and cardiac ischemia‐reperfusion (IR). Cyclophilin D (CyP‐D) is the only protein which has been broadly accepted as a major regulator of the mPTP complex. Therefore, inhibition of CyP‐D is mostly used as a target for inhibition of mPTP opening and thus, prevention of mitochondria‐mediated cell death induced by MI and IR injury. In addition to mPTP regulation, CyP‐D also plays an important physiological role and controls cell metabolism through regulation of glucose uptake, fatty acid oxidation, and mitochondrial bioenergetics. Growing data on the physiological role of CyP‐D and mPTP opening as well as failure of recent CIRCUS (Cyclosporine and Prognosis in Acute Myocardial Infarction Patients) clinical trials when cyclosporin A (CsA) failed to protect the heart in STEM patients, indicates the necessity for further studies elucidating the role of CyP‐D inhibition to exert cardioprotection against IR injury. Here, we hypothesized that inhibition of CyP‐D may have different effects in non‐reperfused MI and reperfused MI (IR). Methods MI was induced in adult female rats (200–250g) by ligation coronary artery (CAL) for 30 min followed by 2‐ and 28‐day post‐surgery with or without reperfusion. The animals were studied in the following groups: i) Sham (S, no MI, n=6 and n=11 for 2 and 28 days, respectively); ii) SS (Sham+SfA, n=5 and n=11 for 2 and 28 days, respectively); iii) MI (no reperfusion, n=4 and n=5 for 2 and 28 days, respectively); iv) MI+SfA (n=4 and n=6 for 2 and 28 days, respectively); v) MI+R (MI+reperfusion, n=4 and n=5 for 2 and 28 days, respectively); and vi) MI+RS (MI+reperfusion+SfA, n=6 and n=7 for 2 and 28 days, respectively). SfA (5mg/kg, IV) was administered at 25 min after a start of sham surgery or MI. Cardiac function was analyzed at 2 and 28 days post‐surgery by echocardiography. Results SfA significantly improved cardiac function (ejection fraction, EF%) (33±5 vs. 53±4, P<0.01) after 2 days, but it had no beneficial effects at 28 days (38±3 vs. 42±4). Likewise, SfA administration to permanent occluded hearts has no effect on EF% at 2 (44±9 vs. 35±9) and 28 (37±3 vs. 44±5) days. SfA administration to control animals reduces cardiac EF% at 2 (69±3 vs. 52±3, P<0.001) and 28 days (66±2 vs. 55±3, P<0.01). Conclusion Our data indicates that inhibition of CyP‐D by SfA has cardioprotective effects on MI at early reperfusion and no effect on MI without short‐ or long reperfusion. Support or Funding Information Supported by NHLBI NIH (SC1HL118669) and NIH MBRS‐RISE Program (R25‐GM061838).