Review on Chamber-Specific Differences in Right and Left Heart Reactive Oxygen Species Handling

Abstract

Reactive oxygen species (ROS) exert signaling character (redox signaling), or damaging character (oxidative stress) on cardiac tissue depending on their concentration and/or reactivity. The steady state of ROS concentration is determined by the interplay between its production (mitochondrial, cytosolic, and sarcolemmal enzymes) and ROS defense enzymes (mitochondria, cytosol). Recent studies suggest that ROS regulation is different in the left and right ventricle of the heart, specifically by a different activity of superoxide dismutase (SOD). Mitochondrial ROS defense seems to be lower in right ventricular tissue compared to left ventricular tissue. In this review we summarize the current evidence for heart chamber specific differences in ROS regulation that may play a major role in an observed inability of the right ventricle to compensate for cardiac stress such as pulmonary hypertension. Based on the current knowledge regimes to increase ROS defense in right ventricular tissue should be in the focus for the development of future therapies concerning right heart failure.

Keywords: MAO; cardiac remodeling; heart failure; oxidative stress; pulmonary hypertension; uncoupling protein.

Figure 1

Sources of reactive oxygen species in cardiomyocytes. (A) Complex I and III of the electron transport chain (ETC) constitutively release ${\text{O}}_2^{.-}$ and complex II can be activated by NOX-dependent ROS. (B) Monoamine oxidase (MAO) generates H₂O₂. (C) Xanthine oxidase (XO) catalyzes a two-step reaction leading to additional release of H₂O₂. (D) Uncoupling of nitric oxide synthase (NOS) leads to generation of ${\text{O}}_2^{.-}$. (E) NADPH oxidase (NOX) generates also ${\text{O}}_2^{.-}$ upon activation.

Figure 2

ROS defense systems in cardiomyocytes. (A) Superoxide dismutases catalyze the formation of H₂O₂ that can be detoxificated by catalase (B). (C) Gluatathione peroxidase (GPX) reduces H₂O₂. (D) Coupled NOS generates NO that neutralizes ${\text{O}}_2^{.-}$.

Figure 3

Differences between right (RV) and left (LV) ventricular cardiomyocytes. LV cardiomyocytes are longer (A), wider (B), larger (C), less mono-nucleated (D), have a reduced cell spreading (E) as adaptation to culture conditions, and a stronger load-free cell shortening (F). Furthermore, mitochondria from RV generate more ROS (G). Data depicted from Schreckenberg et al. (2015) and Schlüter (2016). *p < 0.05 vs. LV.