Introduction to the Series on MicroRNAs in the Cardiovascular System.
Circ Res. 2012 Feb 3;110(3):481-2
Authors: van Rooij E
Abstract
Until recently, microRNAs (miRNAs) were considered to be relatively small players in biological systems by having a balancing function through moderate effects on gene expression levels. However, it has become appreciated that miRNAs are actually much more relevant during both development and disease, which is underscored by the attention they have been receiving. The goal of this thematic review series is to highlight current knowledge of miRNA function during cardiovascular development, their dysregulation under disease conditions and the disease modifying functions they have been shown to exert in the cardiovascular system. These reviews, in addition to discussing the recent advancements in using miRNAs as circulating biomarkers or therapeutic modalities, will hopefully be able to provide a strong basis for future research to further expand our insights into miRNA function in cardiovascular biology.
Circulating MicroRNAs: Novel Biomarkers and Extracellular Communicators in Cardiovascular Disease?
Circ Res. 2012 Feb 3;110(3):483-95
Authors: Creemers EE, Tijsen AJ, Pinto YM
Abstract
In the past few years, the crucial role of different micro-RNAs (miRNAs) in the cardiovascular system has been widely recognized. Recently, it was discovered that extracellular miRNAs circulate in the bloodstream and that such circulating miRNAs are remarkably stable. This has raised the possibility that miRNAs may be probed in the circulation and can serve as novel diagnostic markers. Although the precise cellular release mechanisms of miRNAs remain largely unknown, the first studies revealed that these circulating miRNAs may be delivered to recipient cells, where they can regulate translation of target genes. In this review, we will discuss the nature of the stability of miRNAs that circulate in the bloodstream and discuss the available evidence regarding the possible function of these circulating miRNAs in distant cell-to-cell communication. Furthermore, we summarize and discuss the usefulness of circulating miRNAs as biomarkers for a wide range of cardiovascular diseases such as myocardial infarction, heart failure, atherosclerosis, hypertension, and type 2 diabetes mellitus.
Rarely a new research area has gotten such an overwhelming amount of attention as have microRNAs. Although several basic questions regarding their biological principles still remain to be answered, many specific characteristics of microRNAs in combination with compelling therapeutic efficacy data and a clear involvement in human disease have triggered the biotechnology community to start exploring the possibilities of viewing microRNAs as therapeutic entities. This review serves to provide some general insight into some of the current microRNAs targets, how one goes from the initial bench discovery to actually developing a therapeutically useful modality, and will briefly summarize the current patent landscape and the companies that have started to explore microRNAs as the next drug target.
Recent findings demonstrated the importance of microRNAs (miRNAs) in the vasculature and the orchestration of lipid metabolism and glucose homeostasis. MiRNA networks represent an additional layer of regulation for gene expression that absorbs perturbations and ensures the robustness of biological systems. This function is very elegantly demonstrated in cholesterol metabolism where miRNAs reducing cellular cholesterol export are embedded in the very same genes that increase cholesterol synthesis. Often their alteration does not affect normal development but changes under stress conditions and in disease. A detailed understanding of the molecular and cellular mechanisms of miRNA-mediated effects on metabolism and vascular pathophysiology could pave the way for the development of novel diagnostic markers and therapeutic approaches. In the first part of this review, we summarize the role of miRNAs in vascular and metabolic diseases and explore potential confounding effects by platelet miRNAs in preclinical models of cardiovascular disease. In the second part, we discuss experimental strategies for miRNA target identification and the challenges in attributing miRNA effects to specific cell types and single targets.
Hyperphosphorylation of the Cardiac Ryanodine Receptor at Serine 2808 Is Not Involved in Cardiac Dysfunction After Myocardial Infarction.
Circ Res. 2012 Feb 2;
Authors: Zhang H, Makarewich C, Kubo H, Wang W, Duran J, Li Y, Berretta R, Koch WJ, Chen X, Gao E, Valdivia H, Houser SR
Abstract
Rationale:Abnormal behavior of the cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and heart failure (HF) after myocardial infarction (MI). It has been proposed that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a single residue, Ser-2808, is a critical mediator of RyR dysfunction, depressed cardiac performance, and HF after MI.Objectives:We used a mouse model (RyRS2808A) in which PKA hyperphosphorylation of the RyR2 at Ser-2808 is prevented to determine whether loss of PKA phosphorylation at this site averts post MI cardiac pump dysfunction.Methods and Results:MI was induced in wild-type (WT) and S2808A mice. Myocyte and cardiac function were compared in WT and S2808A animals before and after MI. The effects of the PKA activator Isoproterenol (Iso) on L-type Ca(2+) current (I(CaL)), contractions, and [Ca(2+)](I) transients were also measured. Both WT and S2808A mice had depressed pump function after MI, and there were no differences between groups. MI size was also identical in both groups. L type Ca(2+) current, contractions, Ca(2+) transients, and SR Ca(2+) load were also not significantly different in WT versus S2808A myocytes either before or after MI. Iso effects on Ca(2+) current, contraction, Ca(2+) transients, and SR Ca(2+) load were identical in WT and S2808A myocytes before and after MI at both low and high concentrations.Conclusions:These results strongly support the idea that PKA phosphorylation of RyR-S2808 is irrelevant to the development of cardiac dysfunction after MI, at least in the mice used in this study.
PMID: 22302785 [PubMed - as supplied by publisher]
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