Is CaMKII a link between inflammation and hypertrophy in heart?

Abstract

Myocardial infarction is a major cause of morbidity and mortality in the developing and developed world. Although current interventions have been successful in prolonging life, they are inadequate because mortality is still high among MI patients. The multifunctional Ca(2+)/calmodulin-dependent protein kinase (CaMKII) plays a key role in the structure and contractility of the myocardium. CaMKII activity is increased in MI hearts and CaMKII promotes cardiac hypertrophy and inflammation, processes consistently activated by myocardial injury. Hypertrophy and inflammation are also related to neurohumoral and redox signaling which uncouple CaMKII activation from Ca(2+)/calmodulin dependence. Thus, CaMKII may act as a nodal point for integrating hypertrophic and inflammatory signaling in myocardium.

Figure 1

CaMKII links cardiac hypertrphy and inflammation in post-MI hearts. MI induces danger sensing toll-like receptors that result in production of ROS and activation of NF-κB. NF-κB mediated transcription of cytokines and pro-inflammatory molecules is the major source of inflammation at the site of injury. Inflammatory response promotes ROS production that can render CaMKII independent of Ca2+-dependence, which in turn may enhance the NF-κB activity. In addition, ROS can be produced by induction of TLR and AngII receptors that also affect CaMKII. Cardiac hypertrophy is dependent upon gene expression response by MEF2 transcription factor that is phosphorylated by CaMKII for its activity. Thus, inflammatory cytokines may also induce hypertrophic gene expression. The broken arrow shows a possibility of ROS mediated activation of HDAC may play a role in hypertrophic signaling.