MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.
Background-A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca 2ϩ current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF. Methods and Results-The miRNA transcriptome was analyzed by microarray and verified by real-time reversetranscription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by Ͼ2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca 2ϩ channel ␣1c-and 1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca 2ϩ current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca 2ϩ channel protein subunits. Conclusions-miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca 2ϩ channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF. (Circulation. 2010;122:2378-2387.)
BACKGROUND A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
The Kidney Donor Profile Index (KDPI) has been introduced as an aid to evaluating deceased donor kidney offers, but the relative benefit of high-KDPI kidney transplantation (KT) versus the clinical alternative (remaining on the waitlist until receipt of a lower KDPI kidney) remains unknown. Using time-dependent Cox regression, we evaluated the mortality risk associated with high-KDPI KT (KDPI 71-80, 81-90 or 91-100) versus a conservative, lower KDPI approach (remain on waitlist until receipt of KT with KDPI 0-70, 0-80 or 0-90) in first-time adult registrants, adjusting for candidate characteristics. High-KDPI KT was associated with increased short-term but decreased long-term mortality risk. Recipients of KDPI 71-80 KT, KDPI 81-90 KT and KDPI 91-100 KT reached a ''break-even point'' of cumulative survival at 7.7, 18.0 and 19.8 months post-KT, respectively, and had a survival benefit thereafter. Cumulative survival at 5 years was better in all three high-KDPI groups than the conservative approach (p < 0.01 for each comparison). Benefit of high-KDPI KT was greatest in patients age >50 years and patients at centers with median wait time !33 months. Recipients of high-KDPI KT can enjoy better long-term survival; a high-KDPI score does not automatically constitute a reason to reject a deceased donor kidney.
Among adult first-time kidney transplantation candidates in the United States who were added to the deceased donor kidney transplantation waiting list between 1995 and 2014, disparities in the receipt of live donor kidney transplantation increased from 1995-1999 to 2010-2014. These findings suggest that national strategies for addressing disparities in receipt of live donor kidney transplantation should be revisited.
Background Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)–promoting remodeling. Here, we investigated fibroblast regulation by Ca2+-permeable transient receptor potential canonical-3 (TRPC3) channels. Methods and Results Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (INSC) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca2+ influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca2+ removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5′ promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression. Conclusions TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca2+ influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.
We have previously found that the ether-a-go-go related gene (ERG), a long QT syndrome gene encoding a key K ؉ channel (I Kr ) in cardiac cells, is severely depressed in its expression at the protein level but not at the mRNA level in diabetic subjects. The mechanisms underlying the disparate alterations of ERG protein and mRNA, however, remained unknown. We report here a remarkable overexpression of miR-133 in hearts from a rabbit model of diabetes, and in parallel the expression of serum response factor (SRF), which is known to be a transactivator of miR-133, was also robustly increased. Delivery of exogenous miR-133 into the rabbit myocytes and cell lines produced posttranscriptional repression of ERG, down-regulating ERG protein level without altering its transcript level and caused substantial depression of I Kr , an effect abrogated by the miR-133 antisense inhibitor. Functional inhibition or gene silencing of SRF down-regulated miR-133 expression and increased I Kr density. Repression of ERG by miR-133 likely underlies the differential changes of ERG protein and transcript thereby depression of I Kr , and contributes to repolarization slowing thereby QT prolongation and the associated arrhythmias, in diabetic hearts. Our study provided the first evidence for the pathological role of miR-133 in adult hearts and thus expanded our understanding of the cellular function and pathophysiological roles of miRNAs.Abnormal QT interval prolongation is a prominent electrical disorder and has been proposed a predictor of mortality in patients with diabetes mellitus (DM), 3 presumably because it is associated with an increased risk of sudden cardiac death consequent to lethal ventricular arrhythmias (1-8). Our recent study revealed that the long QT syndrome gene, human ethera-go-go-related gene (HERG) encoding the channel responsible for rapid delayed rectifier K ϩ current (I Kr ), is significantly down-regulated in its expression in diabetic hearts and this down-regulation contributes critically to diabetic repolarization slowing and QT prolongation (9, 10). Strikingly, HERG expressions at transcriptional and post-transcriptional levels diverge in diabetic hearts, with its protein levels being reduced by some 60% while the mRNA levels remaining essentially unaltered (10). These disparate changes indicate that HERG expression is impaired mainly at the post-transcriptional level; however, it remained unclear what are the determinants for the differential regulations of HERG expression at protein and transcript levels.MicroRNAs (miRNAs) are endogenous ϳ22-nucleotide non-coding RNAs that anneal to inexactly complementary sequences in the 3Ј-untranslated regions of target mRNAs of protein-coding genes to regulate gene expression. The major characteristics of miRNA actions is to specify translational repression without affecting the levels of the targeted mRNA (11, 12). Among Ͼ300 miRNAs identified thus far, miR-1 and miR-133 are known to specifically express in adult cardiac and skeletal muscle tissues (13,14). Recent stud...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.