β-Adrenergic Signaling and CPC Function (p 476)
β-Adrenergic stimulation of cardiac progenitor cells is a double-edged sword, say Khan et al.
During heart failure, β-adrenergic stimulation of the heart is increased to aid in contraction, providing temporary relief to weakened heart muscles. In the long-term however, this stimulation causes cardiac myocytes to die. To prevent this damage β-adrenergic blockers are often used to treat heart failure patients. When cardiac myocytes die, they are replaced, albeit slowly, by cardiac progenitor cells. However, it is unclear how exactly these progenitors are affected by β-blockers, or indeed, by β-adrenergic stimulation. Now, Khan et al report that β-adrenergic stimulation induces mouse cardiac progenitor cells to proliferate. But, just like adult cardiac myocytes, the progenitor cells underwent apoptosis as soon as they were induced to differentiate. The investigators found that progenitor cells expressed only one type of β-adrenergic receptor, β1-AR, but upon differentiation, they started to express a second, β2-AR—also found in mature cardiac myocytes. And because these 2 receptors convey separate effects, the authors suggest that a bipartite approach, involving β1-AR activation and β2-AR blockade, could be more effective in treating heart failure.
Pro- and Anti-Apoptotic Signaling of cAMP (p 498)
Zhang et al suggest replacing β-blockers with a PKA inhibitor to treat heart failure.
Much like Khan and colleagues, Zhang et al were interested in the effects of β-adrenergic stimulation and β-blockers on the heart. They knew that long-term β-adrenergic stimulationduring heart failure causes heart cells to die. They also knew that β-blockers prevent this cell death. However, the molecular details of these processes were unclear. β-Adrenergic–induced cell death is thought to be mediated by the stimulation of protein kinase A (PKA), but the effects of β-adrenergic stimulation could also be PKA-independent. To differentiate between PKA and non-PKA effects, the team created transgenic mice expressing a PKA inhibitor. They found that β-adrenergic stimulation in these mice prevented cardiac myocyte death and that the level of protection offered by PKA inhibition was similar to that provided by β-blockers. There was one important distinction, however. The hearts of the transgenic mice when stimulated also exhibited marked ERK activation, which offered further protection to cardiac myocytes. Following myocardial infarction, these PKA-inhibited mice also showed greater improvement in cardiac function than wild-type mice treated with β-blockers. The authors suggest that for treating heart failure patients, PKA-inhibitors may be more effective than β-blockers.
Remodeling of Diabetic Bone Marrow (p 510)
Vascular problems beget more vascular problems in the bone marrow of patients with diabetes, report Spinetti et al.
Cardiovascular complications, such as atherosclerosis and capillary damage are common in diabetes and can have far reaching clinical consequences. In mouse models such capillary damage can affect even the bone marrow. Worse still, in the bone marrow, the failing microvasculature, which feeds the stem cell niche, could reduce the production of progenitors, including pro-angiogenic cells. While it has been shown that circulating progenitor cell levels are suppressed in people with diabetes it is unclear whether, like mice, human bone marrow microvasculature is also affected. Spinetti et al show that bone specimens from diabetes patients do indeed exhibit decreased capillary densities and also contain fewer progenitor cells. The team found that while impaired blood supply did contribute to the reduction in progenitor cell populations, high glucose itself also caused these cells to upregulate a pro-apoptosis pathway. This involved inactivation of microRNA miR-155, and the upregulation of its target - the transcription factor, FOXO3a. Taken together, the data suggest that specific treatments designed to preserve the integrity of capillaries of the bone marrow and the function of progenitor cells could prove important for managing diabetes.
- © 2013 American Heart Association, Inc.