Dynamic Regulation of Cysteine Oxidation and Phosphorylation in Myocardial Ischemia-Reperfusion Injury

Abstract

Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to preserve irreplaceable myocardium, termed cardioprotection, but few, if any, treatments have yielded a substantial reduction in clinical I/R injury. More research is needed to fully understand the molecular pathways that govern cardioprotection. Redox mechanisms, specifically cysteine oxidations, are acute and key regulators of molecular signaling cascades mediated by kinases. Here, we review the role of reactive oxygen species in modifying cysteine residues and how these modifications affect kinase function to impact cardioprotection. This exciting area of research may provide novel insight into mechanisms and likely lead to new treatments for I/R injury.

Keywords: AMPK; Akt; PKA; PKG; heart; ischemia; oxidative stress; reactive oxygen species; redox signaling; reperfusion.

Figure 1

Summary of Cardioprotective Kinase Signaling Pathways. From left to right, receptor tyrosine kinases (RTK) or G-protein coupled receptors (GPCR) stimulate phosphoinositide 3-kinase (PI3K) to produce phosphatidylinositol-(3,4,5) triphosphate (PIP₃) from phosphatidylinositol-(4,5) bisphosphate (PIP₂) and leads to protein kinase B (Akt) activation. Protein kinase A (PKA) activity is induced by GPCR-mediated adenylyl cyclase (AC) stimulation, which produced cyclic adenosine monophosphate (cAMP), regulated by A-kinase-anchoring proteins (AKAP) and phosphodiesterases (PDE). Natriuretic peptides and nitric oxide, respectively, trigger particular and soluble guanylyl cyclase (pGC/sGC) to make cyclic guanosine monophosphate (cGMP), also regulated by PDE and G-kinase-anchoring proteins (GKAP), and initiate protein kinase G (PKG) activity. Finally, AMP kinase (AMPK) is activated by AMP, along with the following kinases: liver kinase B1 (LKB1), calmodulin-dependent protein kinase kinase β(CaMKKβ), and transformation growth factor-β-activated kinase-1 (TAK1).