CXCR4 Regulates BM PC Mobilization Through c-kit (p 1083)
Two types of cell surface receptors work together to keep progenitor cells tucked away in the bone marrow, say Cheng et al.
After ischemic injury, certain progenitor cells in the bone marrow become mobilized, enter the peripheral circulation, and home to the injury site to help with repairs. Until needed, however, the progenitors stay where they are, and researchers have identified two molecular mechanisms that keep them tethered. Whether these two mechanisms were at all related was unknown. Both mechanisms involve interactions between cell surface receptors on the progenitors and their ligands on structural cells of the bone marrow. Cheng et al found that interaction between the first receptor, CXCR4 and its ligand, SDF-1, led to phosphorylation of the second receptor, called c-kit. Consistent with this, a drug called AMD3100, which is known to mobilize progenitors by interacting with CXCR4, reduced levels of phosphorylated c-kit. And, in mice that expressed a constitutively phosphorylated mutant c-kit, AMD3100 lost its mobilizing ability. Because progenitor mobilization is a crucial part of ischemic tissue repair, AMD3100 and other experimental treatments are being investigated for their mobilizing potential. Understanding the molecular nature of the process, thus, offers targets for such treatments.
Timing of Spontaneous Ca Release in Ca Overload (p 1117)
Calcium overload in the heart can cause fatal arrhythmias. Wasserstrom et al have discovered how subcellular calcium events coordinate across the muscle to trigger such undesirable beats.
On a cellular level, the regular beats of the heart start with an electrically triggered action potential that prompts the sarcoplasmic reticulum to release calcium ions that bind to protein machinery that contracts the cell. As well as this controlled calcium release, however, the sarcoplasmic reticulum releases small amounts of calcium spontaneously and apparently stochastically. In conditions of calcium overload, these small calcium release events, or sparks, have been linked with plasma membrane depolarizations that can reach action potential thresholds. For an arrhythmia to occur, however, many cells must work in unison, so it was unclear how stochastic calcium sparks in individual cells could achieve this. Wasserstrom et al measured the spatiotemporal distribution of calcium sparks across muscle cells in intact rat hearts. They found that during calcium overload, the number of sparks increased and the variability in spark timing decreased. This more coordinated timing could, thus, allow cells to simultaneously depolarize, say the authors. They suggest that factors affecting timing, such as SERCA, which reloads calcium into the sarcoplasmic reticulum, could be good targets for antiarrhythmic therapies.
CaMKII Inhibition in Failing Human Myocardium (p 1150)
Inhibiting CaMKII activity could be a means to improve functionality in failing human hearts, say Sossalla et al.
CaMKII is a protein kinase that regulates many components of the calcium-handling cycle of cardiomyocytes. Levels of CaMKII have been reported to be elevated in failing human hearts, but researchers were not sure whether this elevation was some sort of activated compensatory mechanism or whether it was associated with the pathologic process itself. Evidence from mouse and rabbit models of heart failure and from transgenic mice that overexpress CaMKII lent support to the latter possibility. Sossalla et al have now investigated CaMKII's effects in failing human hearts. CaMKII was, indeed, elevated in both ventricles and was associated with reduced calcium load in the sarcoplasmic reticulum. The authors found that the sarcoplasmic reticulum was releasing more calcium than usual, and this was attributable to increased phosphorylation of a calcium channel, called ryanodine receptor, in the sarcoplasmic reticulum's membrane. The ryanodine receptor is a known target of CaMKII activity, and inhibiting CaMKII not surprisingly stemmed the calcium leak. More importantly, inhibiting CaMKII also improved contractility in the failing heart tissue. The authors, therefore, suggest that inhibition of CaMKII may be a new strategy in the fight against heart failure.
Written by Ruth Williams
- © 2010 American Heart Association, Inc.