Published online Sep 26, 2018. doi: 10.4330/wjc.v10.i9.97
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
To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury.
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.
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.
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.