GDF11 Does Not Rescue Pathological Hypertrophy (p 926)
Contrary to prior research, GDF11 does not make old hearts more youthful, say Smith et al.
Heart function declines with age, and a recent study suggested that pathological hypertrophy due to aging may be due to a reduction in the blood levels of growth and differentiation factor 11 (GDF11). That study also reported that boosting levels of GDF11 in aged mice could reverse age-induced hypertrophy. However, the results of the study have been called into question as other investigators have been unable to reproduce the findings. Indeed, in a follow-up study, researchers found that GDF11 levels were increased in aging mice. To address this discrepancy, Smith and colleagues treated two-year-old mice with GDF11 for a month. They measured the size of the animals’ cardiomyocytes, the size of their hearts and their heart function before and after treatment. They found that while older mice do have larger (heavier) hearts than younger mice they also have heavier bodies. However, they found no pathological hypertrophy in the older mice. Treatment with GDF11 did not reduce heart or myocyte size nor did it improve cardiac function. Moreover, in cultured cardiomyocytes, GDF11 treatment was unable to reverse hypertrophy and in fact increased the size of the cells. The researchers conclude that GDF11 is unlikely to be a worthwhile component of any anti-aging elixirs.
Plaque LDL-Metabolism During Regression (p 933)
Bartels et al examine how LDL-lowering treatments alter atherosclerotic plaque function.
Atherosclerotic plaques form when low-density lipoprotein (LDL) particles cross the endothelial walls of blood vessels and trigger recruitment of inflammatory cells (monocytes) in the subintimal space. Once lodged in the vessel wall, monocytes turn into macrophages that engulf and digest LDL, but the local inflammation also increases the permeability of the vessel wall causing a further influx of LDL and plaque growth. LDL-lowering drugs like statins reduce cardiovascular mortality and morbidity associated with atherosclerosis considerably, yet the size of the plaques reduces only modestly. Bartels and colleagues therefore examined how LDL-lowering therapy affects atherosclerotic plaques. They found that when mice with atherosclerosis were subjected to an LDL-lowering treatment a decrease in plaque size was evident only after four weeks. This size reduction was accompanied by a decrease in the plaque’s lipid content and number of foam cells—macrophages filled with fat. However, after just one week of treatment there was already an improvement in the barrier function of the lesions—shown by the fact that influx and degradation of exogenous LDL particles was reduced. The authors conclude that changes in the barrier function and metabolism within lesions precede plaque regression, and suggest that a greater understanding of these changes could identify new drug targets.
COP9 Promotes Misfolded Protein Degradation (p 956)
Su et al identify a protein quality control mechanism in heart cells that may help prevent cardiomyopathies.
Disposal of misfolded proteins is essential for the health of a cell. Indeed aberrant aggregates of misfolded proteins in heart cells have been linked to cardiomyopathy and heart failure. Although cells employ a variety of mechanisms to get rid of misfolded proteins, the main one is the proteasome, which recognizes and degrades proteins tagged with ubiquitin (by ubiquitin ligases). A family of ubiquitin ligases called cullen-RING ligases (CRLs) is known to be under the control of a protein complex called the COP9 signalosome (CSN). However, whether CSN actually drives ubiquitination and protein degradation was a missing piece of the puzzle. Now, using mice genetically engineering to decrease CSN function in the heart, Su and colleagues show that degradation of a misfolded reporter protein was impaired in the absence of CSN. The team also found that diminished CSN function exacerbated symptoms in a mouse model of desmin-related cardiomyopathy—a disease characterized by misfolded protein aggregation. The model mice express a misfolded version of desmin-associated protein CryAB. CSN deficiency increased both the abundance and size of CryAB aggregates while reducing CryAB ubiquitination. Based on these findings, the authors suggest that CSN and CRL might be useful therapeutic targets for boosting the ability of diseased heart cells to get rid of trash proteins.
- © 2015 American Heart Association, Inc.