Redox Control of Cardiac Excitability

Abstract

Reactive oxygen species (ROS) have been associated with various human diseases, and considerable attention has been paid to investigate their physiological effects. Various ROS are synthesized in the mitochondria and accumulate in the cytoplasm if the cellular antioxidant defense mechanism fails. The critical balance of this ROS synthesis and antioxidant defense systems is termed the redox system of the cell. Various cardiovascular diseases have also been affected by redox to different degrees. ROS have been indicated as both detrimental and protective, via different cellular pathways, for cardiac myocyte functions, electrophysiology, and pharmacology. Mostly, the ROS functions depend on the type and amount of ROS synthesized. While the literature clearly indicates ROS effects on cardiac contractility, their effects on cardiac excitability are relatively under appreciated. Cardiac excitability depends on the functions of various cardiac sarcolemal or mitochondrial ion channels carrying various depolarizing or repolarizing currents that also maintain cellular ionic homeostasis. ROS alter the functions of these ion channels to various degrees to determine excitability by affecting the cellular resting potential and the morphology of the cardiac action potential. Thus, redox balance regulates cardiac excitability, and under pathological regulation, may alter action potential propagation to cause arrhythmia. Understanding how redox affects cellular excitability may lead to potential prophylaxis or treatment for various arrhythmias. This review will focus on the studies of redox and cardiac excitation. Antioxid. Redox Signal. 18, 432-468.

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

“…Other candidates therefore include accessory protein‐mediated effects; for example, S100A and sorcin are both Ca 2+ binding proteins known to modulate RyR open probability independent of phosphorylation status 38, 39, 40. Moreover, several of the proteins involved in the excitation contraction coupling of cardiomyocytes have been shown to be influenced by oxidative modifications 41. Differences in antioxidant enzyme activity and oxidative stress in the MI patients, previously established,42 could possibly alter the activation state of CaMKII, as oxidation of CaMKII (at methionine 281/282) increases its activity and consequently causes more leaky RyR channels independent of Thr‐286 phosphorylation 43.…”

Mechanisms of Sudden Cardiac Death

“…38, 39 Figure 3 illustrates the major ROS synthesis pathways in cardiac myocytess. NADPH oxidases are membrane-bound enzymes that use NADH or NADPH as the electron donor to generate O 2 •− from O 2 .…”

“…194 In contrast to RyR2, SERCA activity is reduced upon increased cardiac ROS, 195–197 which can be, at least in part, attributed to reduced ATP supply for SERCA pump owing to mitochondrial dysfunction. 38 Cardiac NCX, which normally extrudes Ca 2+ from cytosol in exchange for Na + , has been shown to be activated in the reverse mode by increased oxidative stress, thereby increasing cytosolic [Ca 2+ ] (Table 2, and Figure 5). 198, 199 …”

Thioredoxins in cardiovascular disease

“…ROS may alter the function of ion channels that control cardiac excitability, resulting in arrhythmias (Aggarwal and Makielski 2013). Atrial fibrillation is a very prevalent arrhythmia that increases with age.…”