Background-Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Methods and Results-Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. Conclusions-Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesisand is suitable for therapeutic intervention in the setting of ischemic heart disease. (Circulation. 2011;124:720-730.)Key Words: myocardial infarction Ⅲ microRNAs Ⅲ angiogenesis Ⅲ antagomir Ⅲ gene expression Ⅲ heart failure M yocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. MI leads to scar formation and left ventricular remodeling, including cardiac dilatation, contractile dysfunction, cardiomyocyte hypertrophy, and fibrosis. 1 Tissue hypoxia triggers endothelial apoptosis, and insufficient capillary density further contributes to an increase of infarct size and left ventricular dysfunction. [2][3][4] Clinical Perspective on p 730MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that regulate a substantial fraction of the genome by binding to the 3Ј untranslated region (3ЈUTR) of frequently coordinately acting target messenger RNAs. 5 MiRNAs have been identified as valuable therapeutic targets in a variety of diseases, including cardiovascular disease. 6 -12 Inhibition of miRNA processing by genetic knockdown of Dicer expression impairs endothelial functions and angiogenesis. [13][14][15] Certain miRNAs are important regulators of endothelial function, especially angiogenesis. 7,13-17 A subset of miRNAs is regulated by tissue oxygen levels, and miR-24 is activated by hypoxic conditions via the hypoxia-inducible factor 1 (HIF-1). 18 Although miR-24 is expressed in a variety Received April 19, 2011; accepted June 7, 2011 Table I). The small RNA...
Transcription of a large part of the human genome results in RNA transcripts that have limited or no protein-coding potential. These include long noncoding RNAs (lncRNAs), which are defined as being ≥200 nucleotides long. Unlike microRNAs, which have been extensively studied, little is known about the functional role of lncRNAs. However, studies over the past 5 years have shown that lncRNAs interfere with tissue homeostasis and have a role in pathological processes, including in the kidney and heart. The developmental expression of the microRNA sponge H19, for example, is altered in the kidneys of embryos carried by hyperglycaemic mothers, and the lncRNA Malat1 regulates hyperglycaemia-induced inflammation in endothelial cells. Putative roles for other lncRNAs have been identified in conditions such as heart failure, cardiac autophagy, hypertension, acute kidney injury, glomerular diseases, acute allograft rejection and renal cell carcinoma. This Review outlines our current understanding of the role and function of lncRNAs in kidney and cardiovascular disease as novel important regulators and potential therapeutic entry points of disease progression.
Chronic kidney disease (CKD) is characterized by tubulointerstitial deposition of extracellular matrix, tubular atrophy and dilatation; the replacement of organ architecture by connective tissue results in progressive loss of organ function. Micro (mi)RNAs are important mediators of tissue fibrosis under various pathological conditions and are of potential therapeutic relevance. These short, noncoding nucleotides (∼22 bases) regulate target messenger RNAs at the post-transcriptional level. Several hundred miRNAs regulate a considerable amount of the human genome and are involved in virtually all biological processes, including cellular proliferation, apoptosis and differentiation. Thus, miRNA deregulation often results in impaired cellular function and development of disease. Here, we summarize the current knowledge on the role of miRNAs in CKD, with particular emphasis on hypertensive kidney disease, diabetic nephropathy, glomerular biology, and IgA nephropathy. Identification of miRNA regulation and function in renal pathology may pinpoint miRNAs as new therapeutic targets in kidney fibrosis and related diseases. A new class of RNA therapeutics, that is, miRNA modulators (such as antagomirs) have been developed, which enable specific targeting of miRNAs and respective downstream gene networks in vivo, thus influencing the mechanisms that underlie disease initiation or progression. The therapeutic potential of miRNA-based treatment strategies in CKD are discussed.
Patients with moderate CKD under specialist care have a high disease burden. Improved diagnostic accuracy, rigorous management of risk factors and unravelling of the genetic predisposition may represent strategies for improving prognosis.
SummaryBackground and objectives MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. MicroRNAs are present in the blood in a remarkably stable form. We tested whether circulating miRNAs in the plasma of critically ill patients with acute kidney injury (AKI) at the inception of renal replacement therapy are deregulated and may predict survival. Design, setting, participants, & measurementsWe profiled miRNAs using RNA isolated from the plasma of patients with AKI and healthy controls. The results were validated in 77 patients with acute kidney injury, 30 age-matched healthy controls, and 18 critically ill patients with acute myocardial infarction by quantitative real-time PCR.Results Circulating levels of miR-16 and miR-320 were downregulated in the plasma of kidney injury AKI patients, whereas miR-210 was upregulated compared with healthy controls (all P Ͻ 0.0001) and disease controls (miR-210 and miR-16: P Ͻ 0.0001; miR-320: P ϭ 0.03). Cox regression (P Ͻ 0.05) and Kaplan-Meier curve analysis (P ϭ 0.03) revealed miR-210 as an independent and powerful predictor of 28-day survival.Conclusions Circulating miRNAs are altered in patients with kidney injury AKI. MiR-210 predicts mortality in this patient cohort and may serve as a novel biomarker AKI reflecting pathophysiological changes on a cellular level.
MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. Circulating miRNAs are remarkably stable in the blood. We tested whether miRNAs are also detectable in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection. We profiled urinary miRNAs of stable transplant patients and transplant patients with acute rejection. The miR-10a, miR-10b and miR-210 were strongly deregulated in urine of the patients with acute rejection. We confirmed these data in urine of a validation cohort of 62 patients with acute rejection, 19 control transplant patients without rejection and 13 stable transplant patients with urinary tract infection by quantitative RT-PCR. The miR-10b and miR-210 were downregulated and miR-10a upregulated in patients with acute rejection compared to controls. Only miR-210 differed between patients with acute rejection when compared to stable transplant patients with urinary tract infection or transplant patients before/after rejection. Low miR-210 levels were associated with higher decline in GFR 1 year after transplantation. Selected miRNAs are strongly altered in urine of the patients with acute renal allograft rejection. The miR-210 levels identify patients with acute rejection and predict long-term kidney function. Urinary miR-210 may thus serve as a novel biomarker of acute kidney rejection.
Type 1 diabetic pediatric patients revealed a significant deregulation of miR-21, miR-126, and miR-210 in plasma and urinary samples, which might indicate an early onset of diabetic-associated diseases.
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