Author + information
- Jason C. Kovacic, MD, PhD∗ ()
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, and the Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Jason C. Kovacic, Cardiovascular Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, New York 10029.
Sometimes, fields of scientific inquiry suddenly appear on the basis of a new piece of equipment, technique, or approach. The direction of such research is often dictated by the new tool’s nature rather than important scientific questions. This research will endure if it leads to subsequent discovery; if not, it will be discarded. Conversely, exciting new avenues of research may spring from seminal scientific discoveries destined to reshape the way we approach biology and disease, with the available tools and technologies barely adequate to probe fundamental new questions that arise. The discovery of micro–ribonucleic acid (miRNA) in the early 1990s falls squarely into the latter category (1).
The miRNAs belong to the family of noncoding RNAs and are highly conserved, small (∼22 nucleotides), single-stranded RNAs that modulate gene expression. Their usual mode of action is to bind to the 3' untranslated regions of specific target messenger RNAs (mRNAs [the RNA moiety fated to be translated into protein]) to suppress mRNA activity and translation, thereby governing protein expression.
As with mRNA and other RNA moieties, miRNAs may play a local intracellular role in regulating gene expression within the same cell that produces them. However, miRNAs also exist in extracellular locations such as blood, urine, and other bodily fluids (2,3). Furthermore, although mRNAs are highly unstable when outside the intracellular milieu, miRNAs may exist in a stable extracellular form, protected from degradation. Indeed, nature seems to have gone to great lengths to protect certain extracellular miRNAs from degradation, with multiple protective mechanisms identified, including association with other complexes, such as high-density lipoprotein (HDL) particles (4), Argonaute-2 (5), or packaging in lipid vesicles or particles (6).
With this identification as a stable entity in these extracellular compartments, researchers were quick to investigate associations between circulating miRNAs and various forms of cardiovascular disease (CVD). In just a few years, accumulating evidence has demonstrated strong associations between levels of specific circulating miRNAs and acute myocardial infarction, coronary artery disease, heart failure, stroke, hypertension, and other CVDs (as reviewed by Creemers et al. ). Although miRNAs are exciting in this context and offer great promise as biomarkers of disease, an important series of questions has arisen from this research that relates specifically to extracellular miRNAs in the circulation:
• From where in the body do these circulating miRNAs originate?
• Do circulating miRNAs serve a predetermined biologic purpose?
• Do circulating miRNAs have biologic targets, and what are they?
These questions are especially poignant, as the seemingly elaborate and unique mechanisms that exist to protect circulating extracellular miRNAs from degradation can be taken as strong (albeit indirect) evidence to suggest that they play a major biologic role.
In this issue of the Journal, Shan et al. (8) provide answers to these questions. Their study began with an astute, earlier observation that miR-223 can be readily detected in vascular cells from the uninjured rat carotid artery, with a further 3-fold increase in miR-223 levels detected 7 days after vascular injury (9). Although miR-223 was only 1 of ∼100 miRNAs that were found to be of potential importance, miR-223 stood out because it was previously thought to be restricted in expression to hematopoietic cells. We now know that hepatocytes also produce miR-223 (10); its production, however, had not been demonstrated in vascular cells. To their credit, Shan et al. chose to pursue this apparent anomaly and were ultimately able to describe the origin, target, and functional role of miR-223 in the vasculature. Although miR-223 has been detected in other tissues, and its effects extend beyond the vasculature (10–12), major new findings of the present study include that: 1) miR-223 is the most abundant miRNA in platelets, monocytes, blood microparticles, and serum, which is consistent across humans, mice, and rats; 2) miR-223 is essentially absent from vascular smooth muscle cells (VSMCs) grown in isolation in vitro, but macrophages produce miR-223 that can be taken up and subsequently identified in VSMCs; 3) miR-223 is more abundant in the serum and diseased arterial wall of both mice and humans with atherosclerosis versus controls without atherosclerosis; 4) miR-223 promotes VSMC apoptosis while inhibiting proliferation and migration; 5) miR-223 binds to insulin-like growth factor 1 receptors, leading to inhibition of the PI3K-Akt pathway (known to be associated with the cell cycle, quiescence, and proliferation); and 6) miR-223 inhibition in vivo leads to increased atherogenesis and increased neointimal formation after arterial injury (8).
Although this research clearly represents an elegant and extensive characterization of miR-223 in the vascular system, not all of these data are novel (4,13,14). Furthermore, miR-223 was recently shown to regulate cholesterol homeostasis, with miR-223 knockout mice exhibiting increased hepatic, total, and HDL cholesterol levels (10). As a potential limitation of the study by Shan et al. (8), it is unclear if the cholesterol-related effects of miR-223 may have affected their in vivo atherogenesis findings. Nevertheless, and despite this concern, this new study’s true strength is that it “puts it all together,” demonstrating a precise pathobiologic miR-223 pathway in VSMCs, making it one of only a few studies to depict the complete extent of how and where a specific circulating miRNA is produced, how it moves from source to target cell, its role in modulating a key intracellular signaling pathway, and finally its biologic effect.
Among the few comparable in vivo vascular studies (Figure 1), Zhang et al. (15) showed that miR-150 is produced by monocytes, packaged into microvesicles, and secreted to be taken up by endothelial cells, where it reduces c-Myb protein expression to ultimately affect endothelial cell migration. Especially relevant to the current paper (8) in the Journal, Tabet et al. (16) recently demonstrated that miR-223 is carried in the blood by HDL and transferred to endothelial cells, where it directly represses intercellular adhesion molecule 1 expression and function. Additional studies have shown that endothelial cell–derived miRNAs also play a role in atherogenesis and vascular remodeling (17–19).
In addition to the vasculature, investigators have begun to dissect pathways of miRNA production, trafficking, and signaling in other biologic systems. Chen et al. (20), for example, have suggested that cardiac progenitor cells produce and secrete miR-451, which can reduce oxidative stress and apoptosis in cardiomyocytes. Nevertheless, publications such as these are few, and our in-depth understanding of the entire “life-cycle” of specific miRNAs in the cardiovascular system remains sparse. Therefore, the current paper represents a small but critical piece of this overall puzzle, demonstrating an important function for miR-223 in the vascular system.
Apart from being an elegant characterization of the vascular life-cycle of miR-223, the work by Shan et al. (8) also highlights the substantial clinical opportunities that have arisen in terms of potentially modulating atherosclerosis and other CVDs by directly targeting endogenous miRNAs or other noncoding RNA moieties (21). Indeed, their finding that inhibition of miR-223 increases atherogenesis argues for the possibility that augmenting miR-223, or increasing its effect or signaling pathway(s), might be a viable therapeutic strategy. However, the specific road to clinical translation for miR-223 may not be straightforward. The fact that miR-223 also decreases VSMC proliferation and migration while increasing apoptosis suggests that caution is required because VSMC apoptosis and impaired function may be associated with weakening of the atherosclerotic fibrous cap and plaque instability in advanced lesions (22). Therefore, although miR-223 might reduce atherosclerotic plaque area, it could be a “double-edged sword” and increase the tendency for plaque rupture.
These issues notwithstanding, while we continue to search for endogenous noncoding RNAs that hold promise as therapeutic targets, it is noteworthy that the clinical landscape is likely about to witness an explosion of novel therapies using the complimentary approach of exogenously administering inhibitory RNAs to modulate gene expression. This new therapeutic wave was set in motion by the discovery of the process of RNA interference (RNAi), which ultimately led to the awarding of the 2006 Nobel Prize in Physiology or Medicine. Numerous studies are now underway seeking to modulate important biologic processes by using RNAi-based therapies, and it seems only a matter of time before the first of these therapies enters our pharmacological armamentarium. Furthermore, in addition to miRNA, several other noncoding RNA moieties are under intense investigation (e.g., long noncoding RNA), and although far less is presently known about these other RNAs, it seems they almost certainly have a major role in the cardiovascular system and may hold promise as therapeutic targets (23).
Whether it is by harnessing the power of RNAi, or by identifying and targeting endogenous noncoding RNAs that are key biologic players, we have good reason to be excited about the remarkable discoveries that have led us to this point and the subsequent advances in our understanding of biology and medicine. Ultimately, this great progress in unlocking the many secrets of noncoding RNA augurs well for the future care of our patients.
The author thanks Dr. Susmita Sahoo for her valuable comments and suggestions. The graphic was created using Servier Medical Art.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Kovacic has received research support from the National Institutes of Health (K08HL111330), AstraZeneca, the American Heart Association (14SFRN20490315; 14SFRN20840000), and The Leducq Foundation (Transatlantic Networks of Excellence Award).
- American College of Cardiology Foundation
- Mitchell P.S.,
- Parkin R.K.,
- Kroh E.M.,
- et al.
- Arroyo J.D.,
- Chevillet J.R.,
- Kroh E.M.,
- et al.
- Diehl P.,
- Fricke A.,
- Sander L.,
- et al.
- Creemers E.E.,
- Tijsen A.J.,
- Pinto Y.M.
- Shan Z.,
- Qin S.,
- Li W.,
- et al.
- Ji R.,
- Cheng Y.,
- Yue J.,
- et al.
- Vickers K.C.,
- Landstreet S.R.,
- Levin M.G.,
- et al.
- Lu Y.,
- Zhang Y.,
- Wang N.,
- et al.
- Chen C.Z.,
- Li L.,
- Lodish H.F.,
- Bartel D.P.
- Zernecke A.,
- Bidzhekov K.,
- Noels H.,
- et al.
- Zhou J.,
- Li Y.S.,
- Nguyen P.,
- et al.
- Uchida S.,
- Dimmeler S.