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Expression of mitochondrial fusion–fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition

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Abstract

Studies on the role of mitochondrial fission/fusion (MFF) proteins in the heart have been initiated recently due to their biological significance in cell metabolism. We hypothesized that the expression of MFF proteins is affected by post-infarction remodeling and in vitro cardiomyocyte hypertrophy, and serves as a target for the Na+/H+ exchanger 1 (NHE-1) inhibition. Post-infarction remodeling was induced in Sprague–Dawley rats by coronary artery ligation (CAL) while in vitro hypertrophy was induced in cardiomyocytes by phenylephrine (PE). Mitochondrial fission (Fis1, DRP1) and fusion (Mfn2, OPA1) proteins were analyzed in heart homogenates and cell lysates by Western blotting. Our results showed that 12 and 18 weeks after CAL, Fis1 increased by 80% (P < 0.01) and 31% (P < 0.05), and Mfn2 was reduced by 17% (P < 0.05) and 22% (P < 0.05), respectively. OPA1 was not changed at 12 weeks, although its expression decreased by 18% (P < 0.05) with 18 weeks of ligation. MFF proteins were also affected by PE-induced hypertrophy that was dependent on mitochondrial permeability transition pore opening and oxidative stress. The NHE-1-specific inhibitor EMD-87580 (EMD) attenuated changes in the expression of MFF proteins in both the models of hypertrophy. The effect of EMD was likely mediated, at least in part, through its direct action on mitochondria since Percoll-purified mitochondria and mitoplasts have been shown to contain NHE-1. Our study provides the first evidence linking cardiac hypertrophy with MFF proteins expression that was affected by NHE-1 inhibition, thus suggesting that MFF proteins might be a target for pharmacotherapy with anti-hypertrophic drugs.

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Abbreviations

ANP:

Atrial natriuretic peptide

ANT:

Adenine nucleotide translocase

CAL:

Coronary artery ligation

COX:

Cytochrome c oxidase

CyP-D:

Cyclophilin D

DRP1:

Dynamin-related protein 1

EMD:

EMD87580

Fis1:

Mitochondrial fission 1 protein

MCT-1:

Monocarboxylate cotransporter 1

MFF:

Mitochondrial fission and fusion

Mfn1 and Mfn2:

Mitofusins 1 and 2

MPT:

Mitochondrial permeability transition

NHE-1:

Na+/H+ exchanger 1

OPA1:

Optic atrophy type 1 protein

PE:

Phenylephrine

RIR:

ROS-induced ROS

ROS:

Reactive oxygen species

RR:

Ruthenium red

α-SA:

α-Skeletal actin

SfA:

Sanglifehrin A

SHR:

Spontaneously hypertensive rats

VDAC:

Voltage dependent anion channel

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Acknowledgments

Dr. M. Karmazyn holds a Tier 1 Canada Research Chair in Experimental Cardiology. This study was supported by a grant from the Institute of Cardiovascular and Respiratory Health of the Canadian Institutes of Health Research to Dr. M. Karmazyn and in part, by the School of Medicine, University of Puerto Rico to Dr. S. Javadov. Dr. A. Kilić was supported by a Fellowship from the Heart and Stroke Foundation of Canada and the Tailored Advanced Collaborative Training in Cardiovascular Science (TACTICS) program.

Conflict of interest

None declared.

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Author notes

  1. J. Craig Hunter

    Present address: Department of Kinesiology, 130 Noll Laboratory, Pennsylvania State University, University Park, PA, 16802, USA

  2. Asad Zeidan

    Present address: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY, 14642, USA

Authors and Affiliations

  1. Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, 00936-5067, USA

    Sabzali Javadov & Nelson Escobales

  2. Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada

    Venkatesh Rajapurohitam, Ana Kilić, J. Craig Hunter, Asad Zeidan, Nazo Said Faruq & Morris Karmazyn

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  1. Sabzali Javadov
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Correspondence to Sabzali Javadov.

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Javadov, S., Rajapurohitam, V., Kilić, A. et al. Expression of mitochondrial fusion–fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition. Basic Res Cardiol 106, 99–109 (2011). https://doi.org/10.1007/s00395-010-0122-3

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