Regulation of Ito,f by NF-κB (p 537)
Panama et al suggest a way to keep cardiac potassium efflux efficient and, thus, to maintain cardiac function during heart disease.
Efflux of potassium ions after rapid depolarization mediates repolarization of the heart. This potassium efflux is invariably impaired in heart disease and hypertrophy, but little is known about the molecular mechanisms responsible for this malfunction. Activation of vasoconstricting α1-adrenergic receptors is known to reduce potassium efflux, as is the inflammatory cytokine tumor necrosis factor (TNF)-α, a known activator of a transcription factor called nuclear factor (NF)-κB. Panama et al were particularly interested in NF-κB, because it is activated in heart disease patients and animal models of hypertrophy and heart failure. The team found that, like TNF-α, α1-adrenergic receptor stimulation also activated NF-κB and that, in turn, NF-κB repressed the expression of a potassium channel auxiliary factor called KChIP2. Lack of available KChIP2 would limit the assembly of necessary potassium channels and reduce potassium efflux, say the authors. Because inhibiting NF-κB prevented the effects of α1-adrenergic receptor stimulation on potassium efflux, this factor might be a possible target for heart disease and hypertrophy therapies in the future.
Integrin αMβ2 Regulates Monocyte Activation (p 544)
Making macrophages stickier impairs their transformation into atherosclerosis-promoting foam cells, say Yakubenko et al.
Infiltration of monocytes and their activation and transformation into fat-gobbling foam cells is a key step in the development of atherosclerotic lesions. Activation of monocytes to macrophages occurs by classical and alternative pathways, and both are implicated in atherogenesis. In this study, the authors focused on the process of alternative activation (by interleukin [IL]-4 and 1L-13). They showed that alternative activation of monocytes induced expression of a foam cell marker called CD36, but that prior stimulation of the monocytes' β2 integrin receptors inhibited this induction. Integrins are cell surface receptors that bind extracellular matrix components. When stimulated, integrins promote the adherence of monocyte to vascular endothelial cells and their migration toward sites of inflammation, such as atherosclerotic plaques. The finding that integrin stimulation was also antiatherogenic (by preventing foam cell formation) was, therefore, somewhat unexpected. The team confirmed the result, however, by showing that mouse monocytes lacking αMβ2 integrins converted more readily to foam cells (at alternative activation) than did wild-type monocytes. Unexpected or not, the finding suggests that integrin stimulation might be a handy adjunct to antiatherosclerotic therapies.
ROS Activate CaMKII to Regulate Late INa (p 555)
Wagner et al discover a new mechanism of sodium imbalance in failing hearts.
The generation of reactive oxygen species (ROS) at sites of ischemia can wreak havoc on the cardiac tissue. Part of the problem is that the ROS lead to loss of sodium and calcium homeostasis, which in turn can lead to contractile dysfunction, arrhythmias, and heart failure. ROS are known to cause accumulation of sodium and calcium in heart cells, but it was not entirely clear how. Wagner et al suspected that a kinase called CaMKII might be involved, at least in the sodium increase. This kinase can activate sodium channels and displays increased expression during heart failure. Furthermore, ROS can oxidize and activate the regulatory domain of CaMKII. The team has now put the pieces together and shows that ROS-induced increase in sodium was, indeed, dependent on CaMKII. Activation of CaMKII by ROS, however, was dependent on ROS-induced calcium release from the sarcoplasmic reticulum. This is because ROS cannot oxidize CaMKII until calcium binds to the kinase and opens up its regulatory domain. The authors suggest that the calcium release occurs through channels called RyRs, which ROS are known to activate. They also suggest that the ROS-activated CaMKII pathway might be a good target for heart failure treatments.
- © 2011 American Heart Association, Inc.