title: Synergistic induction of miR-126 by hypoxia and HDAC inhibitors in cardiac myocytes.
abstract: HDAC inhibitors are under clinical development for the treatment of hypertrophic cardiomyopathy and heart failure although the mechanisms of protection are incompletely understood. Micro-RNA 126, an endothelium-specific miR has been assigned essential developmental roles in the heart by activating survival kinases ERK1/2 and Akt and increasing pro-angiogenic signaling. Here we provide the first evidence that hypoxia and HDAC inhibitors selectively and synergistically stimulate expression of miR-126 in cardiac myocytes. MiR-126 expression was increased 1.7-fold (p<0.05) after 1h of hypoxic exposure and this was further enhanced to 3.0-fold (p<0.01) by simultaneously blocking HDAC with the pan-HDAC inhibitor Tricostatin A (TSA). TSA alone did not increase miR-126. In parallel, hypoxia and TSA synergistically increased p-ERK and p-Akt without effecting VEGF-A level. Knockdown of miR-126 with si-RNA eliminated inductions of p-ERK and p-Akt by hypoxia, whereas miR-126 overexpression mimicked hypoxia and amplified p-ERK and p-Akt in parallel with miR-126. The results suggest that miR-126 is a hypoxia-inducible target of HAT/HDAC and its activation in cardiac myocytes may contribute to cardioprotection by activating cell survival and pro-angiogenic pathways selectively during ischemia.
authors.affiliation: Hangzhou Red Cross Hospital, Zhejiang, China.
authors.forename: Huaping
authors.initials: H
authors.lastname: Shi
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Huilan
authors.initials: H
authors.lastname: Wang
authors.forename: Shoukang
authors.initials: S
authors.lastname: Zhu
authors.forename: Chunming
authors.initials: C
authors.lastname: Dong
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
authors.forename: Jianqin
authors.initials: J
authors.lastname: Wei
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C571458:MIRN126 microRNA, rat; D035683:MicroRNAs; C012589:trichostatin A; D051548:Histone Acetyltransferases; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases