Copyright
©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
NBCe1 Na+-HCO3- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo
Kanimozhi Vairamani, Vikram Prasad, Yigang Wang, Wei Huang, Yinhua Chen, Mario Medvedovic, John N Lorenz, Gary E Shull
Kanimozhi Vairamani, Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3026, United States
Vikram Prasad, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, United States
Yigang Wang, Wei Huang, Department of Pathology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0529, United States
Yinhua Chen, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, United States
Mario Medvedovic, Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0056, United States
John N Lorenz, Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0575, United States
Gary E Shull, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0524, United States
Author contributions: Shull GE, Vairamani K, Wang Y and Lorenz JN designed and coordinated the research; Shull GE and Vairamani K wrote the paper; Wang Y, Vairamani K and Huang W performed the ischemia reperfusion studies; Lorenz JN performed the cardiovascular physiology studies; Medvedovic M, Vairamani K and Shull GE performed the RNA Seq analysis; Prasad V and Chen Y established the animal model and provided important critiques of the study; all authors approved the final version of the manuscript.
Supported by NIH grants, No. HL061974 (to Gary E Shull), No. R01HL136025 (to Yigang Wang), No. P30ES006096 (to Mario Medvedovic); funds from the Center for Clinical and Translational Science and Training, University of Cincinnati (to Gary E Shull); and a Research Innovation Seed Grant from the University of Cincinnati (to Gary E Shull and John N Lorenz).
Institutional review board statement: Because human subjects or tissues were not used in this study, approval from the Institutional review board was not required. Ethical issues relating to the animal protocol were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Cincinnati.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Cincinnati (protocol number: 15-07-27-01).
Conflict-of-interest statement: The authors have no conflict of interest related to this manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared according these guidelines.
Open-Access: This article is an open-access article, which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Gary E Shull, PhD, Professor, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524, United States. shullge@ucmail.uc.edu
Telephone: +1-513-5580056 Fax: +1-513-5581885
Received: April 6, 2018
Peer-review started: April 7, 2018
First decision: June 5, 2018
Revised: July 5, 2018
Accepted: July 15, 2018
Article in press: July 17, 2018
Published online: September 26, 2018
Processing time: 178 Days and 15.4 Hours
ARTICLE HIGHLIGHTS
Research background
There is a strong rationale for the hypothesis that inhibition of NBCe1-mediated Na+-HCO3- cotransport activity protects against cardiac ischemia-reperfusion injury. This suggests that inhibition of NBCe1 could become part of a cardioprotective strategy.
Research motivation
Previous studies have been performed using the isolated heart, but there are no in vivo studies supporting the hypothesis that loss of NBCe1 activity is cardioprotective. Such studies are critical if NBCe1 inhibition is to be developed as a therapeutic strategy.
Research objectives
The objective of this study was to test whether loss of NBCe1 in the heart would protect against cardiac ischemia-reperfusion injury in vivo.
Research methods
Gene targeting was used to develop a conditional knockout mouse model in which the NBCe1 gene was ablated in cardiomyocytes. Hemodynamic measurements were performed to assess the effects of cardiac-specific NBCe1 ablation on cardiovascular performance, RNA Seq analysis was used to study changes in the cardiac transcriptome, and histological techniques were used to analyze cardiomyocyte apoptosis in response to ischemia-reperfusion injury.
Research results
NBCe1 ablation did not impair cardiovascular performance and caused only limited changes in the cardiac transcriptome. However, it caused a significant reduction in apoptosis following in vivo cardiac ischemia-reperfusion injury.
Research conclusions
Loss of NBCe1 in heart does not cause any apparent adverse effects, but does have a cardioprotective effect following ischemia and reperfusion in vivo.
Research perspectives
Future studies should focus on whether NBCe1 ablation is cardioprotective following myocardial infarction and whether partial inhibition of NBCe1 can be combined with other treatments that reduce Na+ and Ca2+ loading.
