Isoform Switching of Cytochrome c Oxidase Is Found in the Event of Permanent Atrial Fibrillation

Background: The reason of permanent atrial fibrillation (AF) remains unknown, but hypoxia is suggested to induce AF. The oxygen-dependent expressions of COX4i2 and COX4i1 have been reported to be differentially regulated in response to hypoxia such that the reduced levels of oxygen lead to an increased expression of COX4i2 and degradation of COX4i1. Here, we studied the expression of COX 4i2 and 4i1 isoform switching in myocardial atrial biopsies taken from patients with sinus rhythm (SR) or permanent atrial fibrillation (AF).

Method: HIF-1α, VEGF-B, COX 4i1, and COX 4i2 mRNA expressions were evaluated with qPCR. In the first experimental study, COX 4i2 induction in HeLa 53 cells under hypoxia was studied. Myocardial biopsies were taken from the patients’ right atria with SR (n = 31) and AF (n = 11) during heart surgery. RT-PCR and myocardial oxygen respiration measurements were performed and protein contents of COX 4i1 and COX 4i2 were detected by Western blotting. Patients’ group data were correlated to the findings of gene expressions in parallel.

Results: Examining HeLa-cell-line culture under normoxia and oxygen deprivation during an extended hypoxia showed an increase in isoform COX 4i2 and HIF-1α expression. Patients with permanent AF also had an elevated isoform 4i2 expression along with a decrease of isoform COX 4i1 mRNA expression. But protein content of cytochrome c oxidase (CytOx) subunit 4 was much lower in the AF group, whereas respiration per units remained the same. Nonetheless, the 4i2/4i1 ratio was changed from 0.63 to 1.058. Isoform 4i2 expression was independent of the extent of coronary artery disease. An increase in the left atrial diameter is supposed to alter isoform COX 4i2 expression.

Conclusion: The isoform ratio 4i2/4i1 of CytOx is changed in the right atrium of patients with AF. Alterations in COX 4i2 expression during relative hypoxia in myocardial tissue may serve as a compensatory mechanism resulting in optimized oxygen utilization and an increased efficiency of energy metabolism. Switching in the isoform expression pattern may thus represent a respiratory and/or regeneratory mechanism during AF corresponding to a subsequent switch in the action mode of the ETC. The success of an interventional therapy appears to be dependent on the bioenergetic status of myocardium. Indications for conversion of heart rhythm should be reevaluated with reference to myocardial bioenergetics status especially in case of chronic coronary heart disease and long-lasting heart valve insufficiency.

Publication History

Article published online:
28 January 2023