CaMKII in the cardiovascular system: sensing redox states

Abstract

The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure, and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca(2+)/CaM). Under conditions of sustained exposure to elevated Ca(2+)/CaM, CaMKII transitions into a Ca(2+)/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine-287 in the CaMKII regulatory domain "traps" CaMKII into an open configuration even after Ca(2+)/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca(2+)/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease.

Figure 1

Oxidation and autophosphorylation both convert CaMKII into a Ca²⁺/CaM-independent enzyme by modification of defined CaMKII regulatory domain amino acids.

Figure 2

ROS and CaMKII both increase the slowly inactivating component of I_Na and enhance I_Ca facilitation, leading to action potential duration (APD) prolongation and early (EADs) and delayed (DADs) afterdepolarizations.

Figure 3

Reactive oxygen species and CaMKII in cardiomyocytes.

Figure 4

CaMKII is a likely participant in complex intercellular crosstalk between calcium and ROS signaling mechanisms.

Figure 5

The oxidation state of CaMKII is acutely sensitive to balance between ROS producing and ROS ablating processes

Figure 6

Mechanical and biological factors increase the production of ROS and activate CaMKII in vascular smooth muscle cells, resulting in impaired vessel tone, enhanced inflammatory response, and increased SMC migration, proliferation, and apoptosis.