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Yip HK, Shao PL, Wallace CG, et al. Early intramyocardial implantation of exogenous mitochondria effectively preserved left ventricular function in doxorubicin-induced dilated cardiomyopathy rat. Am J Transl Res. 2020;12(8):4612-4627
Yip, H. K., Shao, P. L., Wallace, C. G., Sheu, J. J., Sung, P. H., & Lee, M. S. (2020). Early intramyocardial implantation of exogenous mitochondria effectively preserved left ventricular function in doxorubicin-induced dilated cardiomyopathy rat. American journal of translational research, 12(8), 4612-4627.
Yip, Hon-Kan, et al. "Early intramyocardial implantation of exogenous mitochondria effectively preserved left ventricular function in doxorubicin-induced dilated cardiomyopathy rat." American journal of translational research vol. 12,8 (2020): 4612-4627.
Yip HK, Shao PL, Wallace CG, Sheu JJ, Sung PH, Lee MS. Early intramyocardial implantation of exogenous mitochondria effectively preserved left ventricular function in doxorubicin-induced dilated cardiomyopathy rat. Am J Transl Res. 2020 Aug 15;12(8):4612-4627. eCollection 2020. PMID: 32913535; PMCID: PMC7476136.
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Am J Transl Res. 2020 Aug 15;12(8):4612-4627. eCollection 2020.

Early intramyocardial implantation of exogenous mitochondria effectively preserved left ventricular function in doxorubicin-induced dilated cardiomyopathy rat.

American journal of translational research

Hon-Kan Yip, Pei-Lin Shao, Christopher Glenn Wallace, Jiunn-Jye Sheu, Pei-Hsun Sung, Mel S Lee

Affiliations

  1. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
  2. Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 83301, Taiwan.
  3. Department of Nursing, Asia University Taichung 41354, Taiwan.
  4. Department of Medical Research, China Medical University Hospital, China Medical University Taichung 40402, Taiwan.
  5. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 83301, Taiwan.
  6. Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital Xiamen 361028, Fujian, China.
  7. Department of Plastic Surgery, University Hospital of South Manchester Manchester, UK.
  8. Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
  9. Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.

PMID: 32913535 PMCID: PMC7476136

Abstract

This study tested the hypothesis that early implantation of mitochondria (Mito) into left myocardium could effectively protect heart against doxorubicin/12 mg/kg-induced dilated cardiomyopathy (DCM) in rat. Adult-male SD rats (n = 18) were equally categorized into group 1 (sham control), group 2 (DCM) and group 3 [DCM + Mito (500 μg/rat intramyocardial injection by day-21 after DCM induction)] and euthanized by day 60. In vitro studies showed that exogenously-transferred Mito was abundantly identified in H9C2 cells. The q-PCR showed significant increase in relative number of mitDNA in Mito-transferred H9C2 cells than in control group (P<0.001). The mRNA-gene and protein expressions of NRF1/NRF2/Tfam/PGC-1α/ERRα/Mfn2 were significantly increased in low-dose Mito-transferred and more significantly increased in high-dose Mito-transferred H29C2 cells than in control group (all P<0.01). Day-60 left-ventricular-ejection-fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1 (P<0.0001). The ratios of lung and heart weights to tibial length and myocardial histopathological findings of fibrotic area/myocardial injured score/γ-H2AX+ cells exhibited an opposite pattern to LVEF among the three groups (all P<0.0001). The myocardial protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein/p22phox), autophagic (beclin-1/Atg-5/ratio of CL3B-II/CL3B-I), and apoptotic/mitochondrial-damaged (cleaved-caspase-3/mitochondrial Bax/cleaved-PARP/cytosolic-cytochrome-C/DRP1/cyclophilin D1) biomarkers exhibited an opposite pattern, whereas the protein expressions of mitochondrial integrity (mitochondrial-cytochrome-C/mitochondrial-complex I/II/III/IV and Mfn2/PGC-1) exhibited an identical pattern to LVEF among the groups (all P<0.001). In conclusion, early Mito therapy effectively preserved LVEF and myocardial integrity in DCM rat.

AJTR Copyright © 2020.

Keywords: Mitochondria; dilated cardiomyopathy; doxorubicin; molecular-cellular perturbations

Conflict of interest statement

None.

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