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Mdivi‐1 mitigates cardiac dysfunction by attenuating mitophagy in diabetes (1155.3)
Author(s) -
Mishra Paras Kumar,
Nandi Shyam,
Chavali Vishalakshi
Publication year - 2014
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.28.1_supplement.1155.3
Subject(s) - mitophagy , autophagy , mitochondrial fission , mitochondrion , pharmacology , diabetic cardiomyopathy , diabetes mellitus , chemistry , apoptosis , medicine , cardiomyopathy , endocrinology , heart failure , biochemistry
Although Mdivi‐1 ameliorates heart failure by inhibiting autophagy, the mechanism of Mdivi‐1 mediated mitigation of cardiac dysfunction in diabetes is unclear. We hypothesize that Mdivi‐1 improves LV function by mitigating mitophagy in diabetic hearts. The three major sequencial steps required for mitophagy are: smaller size of mitochondria (by excessive fission), decrease in ΔΨm (for initiation of mitophagy) and increase in autophagophore formation (induction of beclin‐1 that initiates autophagy pathway). To investigate cardiac mitophagy, we measured dynamin like receptor‐1 (drp1, fission protein), JC1 (for ΔΨm) and beclin1, Atg3, LC3B (for autophagosome) by RT‐qPCR, Immunoblotting(IB) and immunofluoresence (IF) in male C57BL/6J and Ins2+/‐ (spontaneous, chronic,T1D) mice treated with Mdivi‐1 (50mg/kg, ip./day for 7days). The cardiac dysfunction was evaluated by M‐mode echocardiography. For in vitro study, HL1 cardiomyocytes were treated with low (5mM, LG) and high (25mM, HG) dose of glucose, and Mdivi‐1 (50µmol/L for 40 min). In Ins2+/‐ mice, Mdivi‐1 treatment decreases drp1 (IF,3.8±0.6 folds), beclin1 (IB,2.2±0.3 fold), Atg3 (IB,2.05±0.1 fold) and LC3b (IB,3.4±0.2 fold) but increases both %FS (32.6 ± 2.8 vs 42.6 ± 2.9) and %EF (60.7±4.3 vs 79.6±2.9). Mdivi‐1 did not have effect on blood glucose levels. In HL1 cardiomyocytes, Mdivi‐1 significantly decreases hypopolarized (mitophagy prone) mitochondria (JC1 staining green, IF, 2.3±0.1 fold) that prevents initiation of mitophagy in diabetic cardiomyocytes. This is a novel mechanism of Mdivi‐1 mediated mitigation of mitophagy and amelioration of diabetic cardiomyopathy. Grant Funding Source : NIH, HL113281 and HL116205