miR-499–Induced Cardiomyopathy and mRNA Targeting (p 521)
Increased expression of microRNA miR-499 causes cardiomyopathy in mice, report Matkovich et al.
MicroRNAs, or miRs, are small, noncoding RNAs that bind to and suppress the expression of target mRNAs. In many cases, 1 miR can target multiple mRNAs and thus miR dysregulation can have wide-ranging effects. Matkovich et al examined the role of miR-499 in heart failure. Although levels of miR-499 have been reported to be increased in failing heart, the expression of mir-499 in nonfailing heart is variable, leading some researchers to be skeptical of the link. Part of the problem, the authors suggest, is that the analyses of nonfailing heart tissue included hearts that were hypertrophic. The authors have now found that hypertrophic heart tissue from 2 patients also had high levels of miR-499, which might explain the prior confusion. They also found that miR-499 does induce cardiomyopathy—at least in mice. They overexpressed miR-499 to different levels in 3 mouse lines and found that all these strains displayed cardiomyopathy. Transcriptome and proteome analysis identified hundreds of direct and indirect targets of miR-499, many of which were kinases and phosphatases. Identification of these dysregulated proteins and pathways should help to provide insight into the pathology of heart failure.
Proteasome Dysfunction and Reperfusion Injury (p 532)
Inhibiting proteasome activity exacerbates ischemia-reperfusion injury, report Tian et al.
During myocardial ischemia and reperfusion (I/R), the cells are exposed to high oxidative stress, which damages a large number of cardiac proteins. These proteins are tagged for destruction by the proteasome—one of the main waste-disposal systems in cells. However, there have been conflicting reports as to whether proteasome activity can help or hinder the recovery process after I/R injury. To resolve the controversy, Tian et al created a model mouse in which the proteasome exhibits reduced functionality only in cardiomyocytes. These mice were perfectly healthy under normal conditions, but after I/R they exhibited far greater injury and poorer heart function than normal mice—including greater infarct size, greater cell death, and reduced ventricular ejection fraction. The authors suggest that previous reports of protection against I/R injury by pharmacological proteasome inhibition may be attributable to the known anti-inflammatory effect of such inhibition in other tissues. The team concludes that inhibiting proteasome activity may be a beneficial approach to treating I/R injury, but preventing such inhibition in cardiomyocytes is important.
Clearance of Calciprotein Particles (p 575)
Phagocytes keep the circulatory system clear of calcifying particles, report Herrmann et al.
The blood carries an abundance of calcium and other minerals whose levels must be kept in check. Too much calcium can lead to precipitation of crystals and dangerous calcification of the vessels. The plasma protein fetuin-A is known to protect against calcification by binding calcium and forming calciprotein particles (CPPs), but less is known about how these particles are subsequently disposed. Herrmann et al made fluorescently labeled CPPs, injected them into mice, and assessed their clearance from the blood and uptake into organs. Only the liver and spleen showed significant uptake of fluorescence, and the team showed that phagocytic cells in both organs were responsible—Kupffer cells in the liver and macrophages in the spleen. Furthermore, they found that scavenger receptors on phagocyte surfaces were required for CPP uptake. Scavenger receptor–deficient mice were less efficient at clearing CPPs from their circulation. Understanding the CPP clearing process will be important in developing treatments for patients at high risk of calcification, such as those with chronic kidney disease. It may also help in treating atherosclerotic lesions because macrophages in plaques engulf CPPs as well.
- © 2012 American Heart Association, Inc.