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

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 ?g/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-1?/ERR?/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/?-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.

SUBMITTER: Yip HK

PROVIDER: S-EPMC7476136 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yip Hon-Kan HK Shao Pei-Lin PL Wallace Christopher Glenn CG Sheu Jiunn-Jye JJ Sung Pei-Hsun PH Lee Mel S MS

American journal of translational research 20200815 8

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 iden ...[more]

PMID: 32913535

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Project description:Vascular endothelial growth factor (VEGF)-B selectively binds VEGF receptor (VEGFR)-1, a receptor that does not mediate angiogenesis, and is emerging as a major cytoprotective factor.To test the hypothesis that VEGF-B exerts non-angiogenesis-related cardioprotective effects in nonischemic dilated cardiomyopathy.AAV-9-carried VEGF-B(167) cDNA (10(12) genome copies) was injected into the myocardium of chronically instrumented dogs developing tachypacing-induced dilated cardiomyopathy. After 4 weeks of pacing, green fluorescent protein-transduced dogs (AAV-control, n=8) were in overt congestive heart failure, whereas the VEGF-B-transduced (AAV-VEGF-B, n=8) were still in a well-compensated state, with physiological arterial Po(2). Left ventricular (LV) end-diastolic pressure in AAV-VEGF-B and AAV-control was, respectively, 15.0+/-1.5 versus 26.7+/-1.8 mm Hg and LV regional fractional shortening was 9.4+/-1.6% versus 3.0+/-0.6% (all P<0.05). VEGF-B prevented LV wall thinning but did not induce cardiac hypertrophy and did not affect the density of alpha-smooth muscle actin-positive microvessels, whereas it normalized TUNEL-positive cardiomyocytes and caspase-9 and -3 activation. Consistently, activated Akt, a major negative regulator of apoptosis, was superphysiological in AAV-VEGF-B, whereas the proapoptotic intracellular mediators glycogen synthase kinase (GSK)-3beta and FoxO3a (Akt targets) were activated in AAV-control, but not in AAV-VEGF-B. Cardiac VEGFR-1 expression was reduced 4-fold in all paced dogs, suggesting that exogenous VEGF-B(167) exerted a compensatory receptor stimulation. The cytoprotective effects of VEGF-B(167) were further elucidated in cultured rat neonatal cardiomyocytes exposed to 10(-8) mol/L angiotensin II: VEGF-B(167) prevented oxidative stress, loss of mitochondrial membrane potential, and, consequently, apoptosis.We determined a novel, angiogenesis-unrelated cardioprotective effect of VEGF-B(167) in nonischemic dilated cardiomyopathy, which limits apoptotic cell loss and delays the progression toward failure.

Dataset Information

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

Publications

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

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