The Hypoxia-Inducible MicroRNA Cluster miR-199a∼214 Targets Myocardial PPARδ and Impairs Mitochondrial Fatty Acid Oxidation

Abstract

Peroxisome proliferator-activated receptor δ (PPARδ) is a critical regulator of energy metabolism in the heart. Here, we propose a mechanism that integrates two deleterious characteristics of heart failure, hypoxia and a metabolic shift toward glycolysis, involving the microRNA cluster miR-199a∼214 and PPARδ. We demonstrate that under hemodynamic stress, cardiac hypoxia activates DNM3os, a noncoding transcript that harbors the microRNA cluster miR-199a∼214, which shares PPARδ as common target. To address the significance of miR-199a∼214 induction and concomitant PPARδ repression, we performed antagomir-based silencing of both microRNAs and subjected mice to biomechanical stress to induce heart failure. Remarkably, antagomir-treated animals displayed improved cardiac function and restored mitochondrial fatty acid oxidation. Taken together, our data suggest a mechanism whereby miR-199a∼214 actively represses cardiac PPARδ expression, facilitating a metabolic shift from predominant reliance on fatty acid utilization in the healthy myocardium toward increased reliance on glucose metabolism at the onset of heart failure.

Peroxisome Proliferator-activated Receptor-α-mediated Transcription of miR-199a2 Attenuates Endothelin-1 Expression via Hypoxia-inducible Factor-1α

“…The miR-199a2 precursor is transcribed as a Dynamin-3 opposite strand (DNM3os) RNA polymerase II transcript as previously shown for the mouse DNM3 locus (23). The human DNM3os transcript is also predicted to include miR-214 in the same transcription unit (24). Our studies for the first time show that DNM3os and premiR-199a2 transcription was co-regulated by PPAR␣.…”

“…Recent studies by others show that myocardial hypoxia in mice, induced by transverse aortic constriction, led to increased expression of DNM3os and concomitant miR-199a/miR214 expression (24). Herein, it was shown that miR-199a/miR-214 target PPAR␦ mRNA for turnover, thus resulting in decreased PPAR␦ activity leading to defective mitochondrial respiration, as a consequence of flawed fatty acid substrate metabolism.…”

Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

“…Micro-RNA miR-214 can target alternate targets between different models of heart disease, since NCX1 and PPARδ were not targeted by miR-214 in RV from our PAH model but were found to be targets in whole heart in other studies. 13,15 However, analysis of miR-214 target genes revealed derepression of PTEN in the RV of miR-214 −/− male mice (Fig. 7A, 7G) but not in female mice (not shown).…”

141 Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells - evidence of unique microRNA cargos

“…Further, this miRNA cluster is also related to hypoxia by targeting myocardial PPARd and impairing mitochondrial fatty acid oxidation. 37 Taken together, the most expressed miRNA in exosomes from the MML-1 cells may have a potential role in melanoma progression.…”

“…Several miRNAs in this cluster group such as hsamiR-214-3p, hsa-miR-199a-3p and hsa-miR-155-5p have been associated with metastatic phenotype in melanoma. [36][37][38] The detection of these miRNAs were validated in the exosome samples by inclusion of miR-486-5p which is found to be abundantly present in exosomes using SYBR green detection qPCR ( Table 2). The validation data for miR-214-3p is not shown since the melting curve for this miRNA was below threshold and shows the presence of primer dimer formation and other fragmented product when resolved on 1.5% agarose gel (data not shown).…”