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Sci Rep. 2019 Sep 11;9(1):13170. doi: 10.1038/s41598-019-49666-0.

Chronic Pressure Overload Results in Deficiency of Mitochondrial Membrane Transporter ABCB7 Which Contributes to Iron Overload, Mitochondrial Dysfunction, Metabolic Shift and Worsens Cardiac Function.

Author information

1
Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India.
2
Graduate studies, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India.
3
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India.
4
Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India. trsanthosh@rgcb.res.in.
5
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India. trsanthosh@rgcb.res.in.
6
Graduate studies, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India. trsanthosh@rgcb.res.in.
7
Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India. cckartha@gmail.com.

Abstract

We examined the hitherto unexplored role of mitochondrial transporters and iron metabolism in advancing metabolic and mitochondrial dysfunction in the heart during long term pressure overload. We also investigated the link between mitochondrial dysfunction and fluctuation in mitochondrial transporters associated with pressure overload cardiac hypertrophy. Left ventricular hypertrophy (LVH) was induced in 3-month-old male Wistar rats by constriction of the aorta using titanium clips. After sacrifice at the end of 6 and 15 months after constriction, tissues from the left ventricle (LV) from all animals were collected for histology, biochemical studies, proteomic and metabolic profiling, and gene and protein expression studies. LV tissues from rats with LVH had a significant decrease in the expression of ABCB7 and mitochondrial oxidative phosphorylation (mt-OXPHOS) enzymes, an increased level of lipid metabolites, decrease in the level of intermediate metabolites of pentose phosphate pathway and elevated levels of cytoplasmic and mitochondrial iron, reactive oxygen species (ROS) and autophagy-related proteins. Knockdown of ABCB7 in H9C2 cells and stimulation with angiotensin II resulted in increased ROS levels, ferritin, and transferrin receptor expression and iron overload in both mitochondria and cytoplasm. A decrease in mRNA and protein levels of mt-OXPHOS specific enzymes, mt-dynamics and autophagy clearance and activation of IGF-1 signaling were also seen in these cells. ABCB7 overexpression rescued all these changes. ABCB7 was found to interact with mitochondrial complexes IV and V. We conclude that in chronic pressure overload, ABCB7 deficiency results in iron overload and mitochondrial dysfunction, contributing to heart failure.

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