Ca2+ signaling in the myocardium by (redox) regulation of PKA/CaMKII

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.

Silibinin sensitizes TRAIL-mediated apoptosis by upregulating DR5 through ROS-induced endoplasmic reticulum stress-Ca2+-CaMKII-Sp1 pathway

“…However, there is no evidence as to whether the Ca 2+ signaling pathway preliminarily enhances ROS generation. On the other hand, many recent studies have supported excessive generation of ROS via cellular oxidation, and cellular metabolism is required for Ca 2+ dysregulation [ 42 , 43 ]. In the present study, we determined that silibinin/TRAIL promotes ROS generation and causes ER stress, which stimulates the Ca 2+ signaling pathway.…”

The Role of Oxidative Stress in Myocardial Ischemia and Reperfusion Injury and Remodeling: Revisited

“…The pathological role of cardiac redox signaling features contractile and energetic dysfunction, arrhythmia, transcriptional changes, and mitochondrial free radical release, leading to abnormal myocardial calcium homeostasis [ 57 ]. Oxidant mediated impairment of ryanodine receptor is associated with the activation of PKA/CaMKII, leading to the disruption of calcium homeostasis [ 58 ]. Furthermore, ROS derived from NADPH oxidase (NOX) activation in different cardiac pathologies such as ischemia/reperfusion injury activates cell stress-response signaling network that includes p38 mitogen activated protein kinases (MAPK) and c-Jun NH 2 -terminal kinase (JNK) [ 59 ].…”

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

“…It is well known that the cardiac excitation-contraction coupling is highly dependent on Ca 2+ transient, that is handled through an array of ion channels, antiporters and pumps that are finally regulated, at post-translational level, by phosphorylation. Many kinases have been implicated in the regulation of Ca 2+ transient, such as PKA, CamKII and PKC [47][48][49]. New findings highlight the role, overlooked for many years, of phosphatases in the fine tuning of the phosphorylation balance of physiologically relevant targets [45,50,51].…”