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.