miR-33 and Hepatic Lipoprotein Secretion (p 10)
Allen et al advise against targeting miR-33 for decreasing atherosclerotic lesions.
MicroRNAs (miRs) are small RNAs—approximately 22 nucleotides in length—that bind to and suppress the expression of target mRNAs. A number of these have been implicated in regulating several cardiovascular processes. miR-33, for example has been reported to be pro-atherogenic and it has been shown that short-term suppression of this miR in mice increases plasma levels of HDL—the “good” cholesterol. However, contradictory results for miR-33 have also been reported, and now findings by Allen and colleagues support this contradiction. They found that long-term suppression of miR-33 in mice promoted liver secretion of very low-density lipoproteins (VLDLs), or “bad” cholesterol, and that, overexpression of miR-33 in hepatocytes reduced LDL secretion. The team showed that the mRNA encoding NSF, a key lipoprotein vesicle trafficking factor, was directly targeted by miR-33 and that suppression of miR-33 increased NSF expression. The authors conclude that together miR-33 and NSF control the lipoprotein secretory pathway in hepatocytes, but it remains unclear why miR-33 suppression would in one context increase HDL secretion and, in another, VLDL secretion. Nonetheless, the results suggest that simply targeting miR-33 in anti-atherogenic therapies may not be enough to yield desirable outcomes.
Inhibition of mNCE Prevents Heart Failure (p 44)
Inhibiting a mitochondrial sodium-calcium exchanger prevents heart failure, arrhythmia and sudden death in guinea pigs, report Liu et al.
After a myocardial infarction, heart cells increase in size (hypertrophy) to compensate for the injured, dysfunctional tissue. But chronic hypertrophy can eventually lead to dilated myocardium, impaired contractility, arrhythmia and even sudden cardiac death. Mitochondrial dysfunction is considered to be responsible, at least in part, for the failing myocardium because oxidative stress and limited energy production—both regulated by mitochondria—are associated with the condition. It is thought that elevated levels of cytosolic sodium in failing heart cells diminish mitochondrial calcium via the mitochondrial sodium-calcium exchanger, mNCE. Importantly, inhibition of mNCE in cultured cardiomyocytes not only increases energy production but also decreases the levels of reactive oxygen species triggered by high intracellular sodium. Liu et al now show that inhibition of mNCE can also do this in heart cells from a guinea pig model of heart failure. Moreover, they found that the mNCE inhibitor CGP also attenuated cardiac remodeling and preserved heart function in these animals and protected them from arrhythmia and sudden death. 61 percent of the untreated guinea pigs with heart failure suffered sudden death, while only 14 percent of those receiving continuous mNCE inhibition died. Taken together, these results suggest that blocking mNCE activity could be a possible approach to the treatment of heart failure.
Tregs and Macrophage Differentiation Post-MI (p 55)
Boosting Treg activity after myocardial infarction increases survival in mice, report Weirather et al.
After a heart attack, immune cells rush to the injury site in an effort to remove dead and damaged myocardial tissue. If this inflammation is exaggerated, however, it can lead to poor healing and overt remodeling. Regulatory T cells or Tregs are immune-suppressors and thus contribute to the resolution of inflammation. Recent studies have reported that these cells in lymph nodes close to the heart are activated after myocardial infarction but Weirather and colleagues wanted to know whether Tregs are also recruited to the heart itself and whether they contribute to the healing process. They found that myocardial infarctions in mice did indeed result in Treg recruitment to the infarct zone and improved functional recovery. Genetic ablation of Tregs in mice increased infarct sizes and left ventricle dilation. Experimentally increasing Treg activity after infarction, on the other hand, improved scar formation and, importantly, increased survival as well—from 47 percent to 77 percent after eight weeks. Increasing Treg activity also led to the production of M2 macrophages in the heart, which are known to be anti-inflammatory and to promote wound healing. These findings suggest that Treg activation in patients with myocardial infarction could be a novel therapeutic strategy.
- © 2014 American Heart Association, Inc.