Potential mechanisms behind the inverse relationship of phosphorylation and S-glutathionylation at cMyBP-C seen in cardiovascular disease. PKA might have reduced activity in cardiovascular disease due to increased oxidation of Cys residues (mechanism 1), ultimately leading to a reduction in cMyBP-C phosphorylation. Additionally, or alternatively, protein phosphatase, such as PP1 and PP2, might have increased activity with increased ROS (mechanism 2) and led to cMyBP-C hypo-phosphorylation seen in cardiovascular disease. In addition to altered activity of PKA and phosphatase enzymes, localization of these enzymes has been shown to change in response to other oxidative-related pathways and, thus, may play a role (mechanism 3). More directly, elevated ROS causes a decreased ratio of GSH/GSSG, which in turn favors S-glutathionylation and electro-sterically hinders the phosphorylation of cMyBP-C (mechanism 4). Figure made using BioRender.