Exosomes and Paracrine Effects of CD34+ Cells (p 724)
Exosomes are responsible for the angiogenic effects of CD34+ stem cells, report Losordo and colleagues.
Although stem cell transplantation improves the function of injured hearts, the mechanism of their salubrious effects remains mysterious. Too few of these cells are incorporated into the injured tissue to account for the remarkable functional and physiological benefits that are observed. To account for this discrepancy, some investigators have suggested that stem cells secrete trophic factors that promote the growth of new blood vessels or new cells within the injured tissue (paracrine hypothesis). In an effort to explain the paracrine effect of stem cells, Losordo et al collected exosomes secreted by CD34+ stem cells, shown previously to reduce angina and lower the rates of amputation in patients with critical limb ischemia. They report that these exosomes were just as potent as the CD34+ cells in promoting the growth of endothelial cells in culture and in stimulating angiogenesis in vivo. Exosomes from non-CD34+ cells were ineffective. How stem cell–derived exosomes stimulate angiogenesis remains a mystery, but the authors suggest that the role of angiogenic microRNAs (miR-126 and miR-130), sequestered within these vesicles, is one mechanism to explore in future studies.
Peroxiredoxin 2 Ameliorates Atherosclerosis (p 739)
Park et al uncover a unique role of peroxiredoxin 2 in preventing atherosclerotic lesion formation.
Atherosclerotic lesions preferentially develop in areas where blood vessels are branched or curved. Turbulent blood flow in these areas stimulates the production of reactive oxygen species (ROS), which promote leukocyte adhesion to the vessel wall and stimulate the development of atherosclerotic plaques. Park et al show that vascular areas exposed to turbulent flow express high levels of the hydrogen peroxide–removing enzyme peroxiredoxin 2 (Prdx2) and that deletion of this enzyme increases vascular adhesion and the formation of atherosclerotic lesions in apoE-null mice. They report that loss of Prdx2 increases infiltration of immune cells into plaques and that the absence of this enzyme, either in vascular or immune cells, is equally atherogenic. Significantly, deletion of other peroxide-removing enzymes such as glutathione peroxidase and catalase was less harmful than Prdx2 deficiency, suggesting that Prdx-2 has a unique role in removing peroxides from sites at which they can cause the most damage. Such specificity of action may also explain the limited success of attempts to inhibit atherosclerosis by global antioxidant interventions.
Redox Regulation of ATP Synthase (p 750)
Van Eyk and associates identify a mitochondrial redox sensor in failing hearts.
Because of conduction defects, heart failure results in discoordinate contraction of the myocardium. Resynchronization of contraction by biventricular stimulation improves heart function and enhances long-term survival of patients with heart failure. Cardiac resynchronization therapy (CRT) also improves the energetic efficiency of the heart, but the molecular and cellular basis for this improvement remains unknown. In their previous work, Van Eyk et al had found that heart failure in dogs results in partial inhibition of mitochondrial ATP synthase and that this activity could be restored by CRT. They also found that CRT affects several mitochondrial proteins involved in energy production and redox regulation. They now link these two phenomena together, demonstrating that dyssynchronous heart failure results in the formation of disulfide bonds between the α- and the γ-subunits of ATP synthase as well as S-glutathiolation of the α-subunit. These changes were reversed by CRT, which induced S-nitrosation of the protein. The authors suggest that a uniquely reactive cysteine residue (Cys-294), located within the α-subunit of ATP synthase, functions as a redox switch that is able to sense the redox state and adjust energy production accordingly.
Written by Aruni Bhatnagar.
- © 2011 American Heart Association, Inc.