Regulation of signal transduction by reactive oxygen species in the cardiovascular system

Abstract

Oxidative stress has long been implicated in cardiovascular disease, but more recently, the role of reactive oxygen species (ROS) in normal physiological signaling has been elucidated. Signaling pathways modulated by ROS are complex and compartmentalized, and we are only beginning to identify the molecular modifications of specific targets. Here, we review the current literature on ROS signaling in the cardiovascular system, focusing on the role of ROS in normal physiology and how dysregulation of signaling circuits contributes to cardiovascular diseases, including atherosclerosis, ischemia-reperfusion injury, cardiomyopathy, and heart failure. In particular, we consider how ROS modulate signaling pathways related to phenotypic modulation, migration and adhesion, contractility, proliferation and hypertrophy, angiogenesis, endoplasmic reticulum stress, apoptosis, and senescence. Understanding the specific targets of ROS may guide the development of the next generation of ROS-modifying therapies to reduce morbidity and mortality associated with oxidative stress.

Keywords: cardiovascular diseases; oxidative stress; reactive oxygen species; signal transduction.

Figure 1. Oxidative modifications

(Hydrogen Peroxide). Low pKa protein thiols react with H₂O₂ to produce various oxidative modifications. Initial oxidation results in formation of the sulfenic acid functional group, which is subject to s-glutathionylation and disulfide bond formation. Disulfide bonds are also created by PDI and reversed by Trx. Subsequent oxidation of sulfenic acid forms sulfinic acid, which may be reversible by Srx, and sulfonic acid, which is believed to be irreversible. (Superoxide). O₂^•− reversibly reacts with heme Fe³⁺ to form Fe²⁺ + O₂. (Free ROS reactions). Free O₂^•− in the cell is converted to H₂O₂ by SOD and H₂O + O₂ by GPX and catalase. Free O₂^•− can also react with NO to form OONO−.

Figure 2. Redox signaling pathways in migration and adhesion

(Dark Gray) Redox modified proteins. (Illustration Credit: Ben Smith).

Figure 3. Redox signaling pathways in contraction

(Left) VSMC contraction proteins and their relationship to EC-derived NO. (Right) Cardiac contraction proteins. (Dark Gray) Redox modified proteins.

Figure 4. Redox signaling pathways in hypertrophy and proliferation

(Dark Gray) Redox modified proteins. (illustration credit: Ben Smith).

Figure 5. Redox signaling in ER stress and autophagy

(Dark Gray) Redox modified proteins.

Figure 6. Redox signaling in apoptosis and senescence

(Dark Gray) Redox modified proteins.