Alternative Oxidase (AOX): A Tool to Study the Role of Reactive Oxygen Species in Cardiac Remodeling after Ischemia/Reperfusion

Objectives: Cardiac ischemia and reperfusion (I/R) causes heart muscle injuries, which induce organ remodeling eventually leading to contractile failure. Much of the muscle damage occurring in the course of ischemia and reperfusion has been attributed to mitochondrial respiratory dysfunction and the concomitant production of reactive oxygen species (ROS). Alternative oxidase (AOX) is a respiratory enzyme that restores respiratory chain function when impaired thereby blunting ROS production. Hence, AOX was proposed to be a natural rescue mechanism from ischemia and reperfusion injuries and contractile dysfunction.

Methods: To test this assumption, wild-type (WT) and AOX transgenic mice (AOXRosa26) underwent transient left anterior descending coronary artery ligation (LAD) at ~12-weeks and were followed-up for 3 or 9 weeks. Cardiac contractile function was studied using a Langendorff-perfused heart model, mitochondrial respiratory capacity was measured using high-resolution (O2k) respirometry and adaptive organ remodeling was studied using RT-PCR and tissue proteomics. Our data revealed that AOX attenuated mitochondrial ROS load and preserved mitochondrial respiration in post-ischemic tissue. Yet, presence of AOX blunted the gene expression of presumingly stress response genes such as atrial natriuretic peptide (Anp) while pro-fibrotic and pro-apoptotic genes were up-regulated. Finally, tissue proteome analysis indicated altered expression of proteins involved in extracellular matrix remodeling best exemplified for periostin. Periostin was upregulated almost 5-fold in postischemic AOX hearts at 3 weeks, and 17-fold at 9 weeks, while the increase in the corresponding WT hearts was less than 2- and nearly 7-fold after 3 and 9 weeks, respectively.

Conclusion: Our data identified mitochondrial ROS originating from a dysfunctional respiratory chain as a possible effector for postischemic heart remodeling and preservation of contractility.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
19 February 2021