Abstract
Homeostatic cardiac function is maintained by a complex network of interdependent signaling pathways which become compromised during disease progression. Excitation-contraction-coupling, the translation of an electrical signal to a contractile response is critically dependent on a tightly controlled sequence of events culminating in a rise in intracellular Ca2+ and subsequent contraction of the myocardium. Dysregulation of this Ca2+ handling system as well as increases in the production of reactive oxygen species (ROS) are two major contributing factors to myocardial disease progression. ROS, generated by cellular oxidases and by-products of cellular metabolism, are highly reactive oxygen derivatives that function as key secondary messengers within the heart and contribute to normal homeostatic function. However, excessive production of ROS, as in disease, can directly interact with kinases critical for Ca2+ regulation. This post-translational oxidative modification therefore links changes in the redox status of the myocardium to phospho-regulated pathways essential for its function. This review aims to describe the oxidative regulation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and cAMP-dependent protein kinase A (PKA), and the subsequent impact this has on Ca2+ handling within the myocardium. Elucidating the impact of alterations in intracellular ROS production on Ca2+ dynamics through oxidative modification of key ROS sensing kinases, may provide novel therapeutic targets for preventing myocardial disease progression.
Highlights
Homeostatic cardiac function is maintained by a complex network of interdependent signaling pathways which become compromised during disease progression
This review aims to describe the oxidative regulation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and cAMP-dependent protein kinase A (PKA), and the subsequent impact this has on Ca2+ handling within the myocardium
The sequential reduction of molecular oxygen leads to formation of biological forms of reactive oxygen species (ROS) comprising of the superoxide anion (O−2 ), hydrogen peroxide (H2O2) and hydroxyl radical (HO).These forms of ROS are capable of altering cellular signaling by modifying susceptible proteins
Summary
Homeostatic cardiac function is maintained by a complex network of interdependent signaling pathways which become compromised during disease progression. Excitation-contraction-coupling, the translation of an electrical signal to a contractile response is critically dependent on a tightly controlled sequence of events culminating in a rise in intracellular Ca2+ and subsequent contraction of the myocardium Dysregulation of this Ca2+ handling system as well as increases in the production of reactive oxygen species (ROS) are two major contributing factors to myocardial disease progression. For example ROS produced by nicotinamide adenine dinucleotide phosphate-oxidase (NOX) enzymes modulate cardiac transcription factors, cell migration, vascular tone, and cardiac contraction (Aslan and Ozben, 2003; Clempus et al, 2007; Burgoyne et al, 2012) Their excessive production, both transiently, and chronically, are implicated in numerous cardiovascular pathologies such as inflammation, arrhythmias, diabetes, hypertension, atherosclerosis, reperfusion injury, fibrosis, Redox regulation of PKA/CaMKII within the myocardium and diastolic dysfunction (Higashi et al, 2002; Fortuño et al, 2004; Zweier and Talukder, 2006; Birukov, 2009; Frantz et al, 2009; Giacco and Brownlee, 2010; Prysyazhna et al, 2012; Wagner et al, 2013; Murdoch et al, 2014). The pKa of a cysteine thiol is determined by its local tertiary environment, which is lowered by close proximity to basic amino acids lysine, arginine, or histidine
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