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©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
AIM
To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury.
METHODS
An NBCe1 (Slc4a4 gene) conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wildtype (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo IR injury was analyzed after 30 min occlusion of the left anterior descending artery followed by 3 h of reperfusion.
RESULTS
Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in response to β-adrenergic stimulation, and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections.
CONCLUSION
These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against IR injury in vivo .
Core tip: The NBCe1 Na+-HCO3- cotransporter and NHE1 Na+/H+ exchanger both mediate Na+-loading and intracellular pH regulation in cardiomyocytes. Inhibition of NHE1 protects against ischemia-reperfusion (IR) injury, and evidence suggests that loss of NBCe1 activity could also be cardioprotective. We have developed a conditional NBCe1 knockout mouse model and have used it to determine the effects of NBCe1 ablation in cardiac muscle. These studies demonstrate that loss of NBCe1 does not impair cardiac performance. However, cardiomyocyte apoptosis following IR injury in vivo is much lower in hearts that lack NBCe1, thus indicating that loss of NBCe1 is cardioprotective.
