Downregulation of MiR-199a Derepresses Hypoxia-Inducible Factor-1α and Sirtuin 1 and Recapitulates Hypoxia Preconditioning in Cardiac Myocytes

Abstract

MicroRNAs are posttranscriptional gene regulators that are differentially expressed during various diseases and have been implicated in the underlying pathogenesis. We report here that miR-199a is acutely downregulated in cardiac myocytes on a decline in oxygen tension. This reduction is required for the rapid upregulation of its target, hypoxia-inducible factor (Hif)-1α. Replenishing miR-199a during hypoxia inhibits Hif-1α expression and its stabilization of p53 and, thus, reduces apoptosis. On the other hand, knockdown of miR-199a during normoxia results in the upregulation of Hif-1α and Sirtuin (Sirt)1 and reproduces hypoxia preconditioning. Sirt1 is also a direct target of miR-199a and is responsible for downregulating prolyl hydroxylase 2, required for stabilization of Hif-1α. Thus, we conclude that miR-199a is a master regulator of a hypoxia-triggered pathway and can be exploited for preconditioning cells against hypoxic damage. In addition, the data demonstrate a functional link between 2 key molecules that regulate hypoxia preconditioning and longevity.

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

“…Moreover, our study also showed that miR-181a decreases SIRT1 protein levels in mouse liver. Previous studies have shown that SIRT1 can be regulated by multiple miRNAs, such as miR-9, miR-22, miR-34a, miR-132, miR-199a and miR-217 in some different biological processes [27,[30][31][32]. In our experiment, we similarly observed the inhibitory effect of these miRNAs.…”

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

“…Previous work had identified several hypoxia-regulated mRNAs, such as HIF1a and SIRT1, as being direct miR-199a-5p targets in cardiomyocytes. 32 Emphasis was placed on the WNT signaling factors WNT2, FZD4, and JAG1, as these three genes have been shown to have an important role in muscle stem cell Percentage of zebrafish with noticeable pericardial edema WT or Tg(mylz2-miR-199a-5p) Tg fish offspring at 5 dpf. Scale bars denote percentage error of the mean, and samples were analyzed in three separate mating cohorts Figure 7 MiR-199a-5p targets several components of the WNT signaling pathway in muscle.…”

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

“…It is well documented that inducible miR-199a-5p arrests cell proliferation and contributes to cell death (7,8,26,27). Our group and others have previously reported that miR-199a-5p regulates cellular detoxifying systems by targeting multidrug resistance-associated protein 1 (6) and CD44 (12).…”

“…It is expressed in a variety of organs including the brain (6), liver (9), stomach (10), ovarian tissue (11,12), testicular tissue (13), and the cardiovascular system, such as in cardiomyocytes (7,8) and endothelial cells (14,15). Recent evidence revealed that miR-199a-5p plays a critical role in attenuating cell migration and in limiting cancer cell metastasis by targeting receptor tyrosine kinase Discoidin domain receptor-1 (9), Axl (16), and anti-adhesive transmembrane glycoprotein podocalyxin-like protein 1 (13).…”