PMID- 31338525
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20200622
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 97
IP  - 10
DP  - 2019 Oct
TI  - Hypoxia drives cardiac miRNAs and inflammation in the right and left ventricle.
PG  - 1427-1438
LID - 10.1007/s00109-019-01817-6 [doi]
AB  - Alveolar and myocardial hypoxia may be causes or sequelae of pulmonary 
      hypertension (PH) and heart failure. We hypothesized that hypoxia initiates 
      specific epigenetic and transcriptional, pro-inflammatory programs in the right 
      ventricle (RV) and left ventricle (LV). We performed an expression screen of 750 
      miRNAs by qPCR arrays in the murine RV and LV in normoxia (Nx) and hypoxia (Hx; 
      10% O(2) for 18 h, 48 h, and 5d). Additional validation included single qPCR 
      analysis of miRNA and pro-inflammatory transcripts in murine and human RV/LV, and 
      neonatal rat cardiomyocytes (NRCMs). Differential qPCR-analysis (Hx vs. Nx in RV, 
      Hx vs. Nx in LV, and RV vs. LV in Hx) identified nine hypoxia-regulated miRNAs: 
      let-7e-5p, miR-29c-3p, miR-127-3p, miR-130a-3p, miR-146b-5p, miR-197-3p, 
      miR-214-3p, miR-223-3p, and miR-451. Hypoxia downregulated miR-146b in the RV 
      (p < 0.01) and, less so, in the LV (trend; p = 0.28). In silico alignment showed 
      significant binding affinity of miR-146b-5p sequence with the 3'UTR of TRAF6 
      known to be upstream of pro-inflammatory NF-kB. Consistently, hypoxia induced 
      TRAF6, IL-6, CCL2(MCP-1) in the mouse RV and LV. Incubating neonatal rat 
      cardiomyocytes with pre-miR-146b led to a downregulation of TRAF6, IL-6, and 
      CCL2(MCP-1). TRAF6 mRNA expression was also increased by 3-fold in the RV and LV 
      of end-stage idiopathic pulmonary arterial hypertension (PAH) patients vs. 
      non-PAH controls. We identified hypoxia-regulated, ventricle-specific miRNA 
      expression profiles in the adult mouse heart in vivo. Hypoxia suppresses 
      miR-146b, thus de-repressing TRAF6, and inducing pro-inflammatory IL-6 and 
      CCL2(MCP-1). This novel hypoxia-induced miR-146b-TRAF6-IL-6/CCL2(MCP-1) axis 
      likely drives cardiac fibrosis and dysfunction, and may lead to heart failure. 
      KEY MESSAGES: Chouvarine P, Legchenko E, Geldner J, Riehle C, Hansmann G. Hypoxia 
      drives cardiac miRNAs and inflammation in the right and left ventricle. * Hypoxia 
      drives ventricle-specific miRNA profiles, regulating cardiac inflammation. * 
      miR-146b-5p downregulates TRAF6, known to act upstream of pro-inflammatory NF-kappaB. 
      * Hypoxia downregulates miR-146b and induces TRAF6, IL-6, CCL2 (MCP-1) in the 
      murine RV and LV. * The inhibitory regulatory effects of miR-146b are confirmed 
      in primary rat cardiomyocytes (pre-miR, anti-miR) and human explant heart tissue 
      (endstage pulmonary arterial hypertension). * A novel 
      miR-146b-TRAF6-IL-6/CCL2(MCP-1) axis likely drives cardiac inflammation, fibrosis 
      and ventricular dysfunction.
FAU - Chouvarine, Philippe
AU  - Chouvarine P
AD  - Department of Pediatric Cardiology and Critical Care, Hannover Medical School, 
      Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
FAU - Legchenko, Ekaterina
AU  - Legchenko E
AD  - Department of Pediatric Cardiology and Critical Care, Hannover Medical School, 
      Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
FAU - Geldner, Jonas
AU  - Geldner J
AD  - Department of Pediatric Cardiology and Critical Care, Hannover Medical School, 
      Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
FAU - Riehle, Christian
AU  - Riehle C
AD  - Department of Cardiology and Angiology, Hannover Medical School, 
      Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
FAU - Hansmann, Georg
AU  - Hansmann G
AUID- ORCID: 0000-0003-0709-3935
AD  - Department of Pediatric Cardiology and Critical Care, Hannover Medical School, 
      Carl-Neuberg-Str. 1, 30625, Hannover, Germany. georg.hansmann@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190723
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (MicroRNAs)
RN  - 0 (TNF Receptor-Associated Factor 6)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/metabolism
MH  - Gene Expression Profiling/*methods
MH  - *Gene Expression Regulation
MH  - Heart Ventricles/metabolism
MH  - Humans
MH  - Hypertension, Pulmonary/genetics/metabolism/pathology
MH  - Hypoxia
MH  - Inflammation/*genetics/metabolism
MH  - Interleukin-6/genetics/metabolism
MH  - Male
MH  - Mice
MH  - MicroRNAs/*genetics
MH  - Myocardium/*metabolism/pathology
MH  - Rats
MH  - TNF Receptor-Associated Factor 6/genetics/metabolism
OTO - NOTNLM
OT  - Cardiomyocytes
OT  - Hypoxia
OT  - Inflammation
OT  - Ventricle-specific
OT  - microRNA
EDAT- 2019/07/25 06:00
MHDA- 2020/06/23 06:00
CRDT- 2019/07/25 06:00
PHST- 2018/08/27 00:00 [received]
PHST- 2019/07/02 00:00 [accepted]
PHST- 2019/06/20 00:00 [revised]
PHST- 2019/07/25 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/07/25 06:00 [entrez]
AID - 10.1007/s00109-019-01817-6 [pii]
AID - 10.1007/s00109-019-01817-6 [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2019 Oct;97(10):1427-1438. doi: 10.1007/s00109-019-01817-6. 
      Epub 2019 Jul 23.