Hydrogen Peroxide Sensing and Signaling by Protein Kinases in the Cardiovascular System

Abstract

Significance: Oxidants were once principally considered perpetrators of injury and disease. However, this has become an antiquated view, with cumulative evidence showing that the oxidant hydrogen peroxide serves as a signaling molecule. Hydrogen peroxide carries vital information about the redox state of the cell and is crucial for homeostatic regulation during health and adaptation to stress. Recent Advances: In this review, we examine the contemporary concepts for how hydrogen peroxide is sensed and transduced into a biological response by introducing post-translational oxidative modifications on select proteins. Oxidant sensing and signaling by kinases are of particular importance as they integrate oxidant signals into phospho-regulated pathways. We focus on CAMKII, PKA, and PKG, kinases whose redox regulation has notable impact on cardiovascular function. Critical Issues: In addition, we examine the mechanism for regulating intracellular hydrogen peroxide, considering the net concentrations that may accumulate. The effects of endogenously generated oxidants are often modeled by applying exogenous hydrogen peroxide to cells or tissues. Here we consider whether model systems exposed to exogenous hydrogen peroxide have relevance to systems where the oxidant is generated endogenously, and if so, what concentration can be justified in terms of relevance to health and disease. Future Directions: Improving our understanding of hydrogen peroxide signaling and the sensor proteins that it can modify will help us develop new strategies to regulate intracellular signaling to prevent disease.

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

“…Finally, the validity of H 2 O 2 as clinically relevant oxidative stress may be questioned. However as stressed previously [40] levels 100–150 μM concentrations of H 2 O 2 have been suggested to be clinically relevant to mimic reversible pro-oxidant pathological states [41]. Indeed H 2 O 2 has been used successfully to assess the influence of oxidative stress in AF in diverse animal models [23,25,42,43].…”

Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

“…Substrate selection, i.e., glucose-FAs, and insulin have a direct impact on diabetic muscle energetics/redox status, thereby affecting contractile performance. Mechanistically, ROS can induce post-translational modifications of key-components of excitation-contraction (EC) coupling, shaping their functional performance (13,14). Moreover, mitochondrial failure to provide enough ATP underscores abnormal function of Ca 2ϩ channels and pumps in the diastolic and systolic dysfunction associated with diabetic cardiomyopathy (10,47).…”

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

“…Recent evidence suggests that myocardial production of hydrogen peroxide (H 2 O 2 ) may be a signal responsible for the near lockstep increases of coronary blood flow that accompany intensified metabolic demand (21,40,47). H 2 O 2 is generated in a variety of cellular processes and may be the primary transmitter of physiological redox signals (9,45). For example, in coronary microvessels, H 2 O 2 is an endogenous hyperpolarizing factor released by mechanical and paracrine stimulation of the endothelium (31,46).…”