PMID- 24447911 OWN - NLM STAT- MEDLINE DCOM- 20141104 LR - 20220223 IS - 1873-3913 (Electronic) IS - 0898-6568 (Print) IS - 0898-6568 (Linking) VI - 26 IP - 5 DP - 2014 May TI - Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration. PG - 933-41 LID - S0898-6568(14)00016-3 [pii] LID - 10.1016/j.cellsig.2014.01.005 [doi] AB - The omega-3 polyunsaturated fatty acids (omega-3 fatty acids) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported to inhibit or delay the progression of cardiovascular diseases, including myocardial fibrosis. Recently we reported that angiotensin II (Ang II) promotes cardiac fibroblast (CF) migration by suppressing the MMP regulator reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), through a mechanism dependent on AT1, ERK, and Sp1. Here we investigated the role of miR-21 in Ang II-mediated RECK suppression, and determined whether the omega-3 fatty acids reverse these effects. Ang II induced miR-21 expression in primary mouse cardiac fibroblasts (CFs) via ERK-dependent AP-1 and STAT3 activation, and while a miR-21 inhibitor reversed Ang II-induced RECK suppression, a miR-21 mimic inhibited both RECK expression and Ang II-induced CF migration. Moreover, Ang II suppressed the pro-apoptotic PTEN, and the ERK negative regulator Sprouty homologue 1 (SPRY1), but induced the metalloendopeptidase MMP2, all in a manner that was miR-21-dependent. Further, forced expression of PTEN inhibited Akt phosphorylation, Sp1 activation, and MMP2 induction. Notably, while both EPA and DHA reversed Ang II-mediated RECK suppression, DHA appeared to be more effective, and reversed Ang II-induced miR-21 expression, RECK suppression, MMP2 induction, and CF migration. These results indicate that Ang II-induced CF migration is differentially regulated by miR-21-mediated MMP induction and RECK suppression, and that DHA has the potential to upregulate RECK, and therefore may exert potential beneficial effects in cardiac fibrosis. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Siddesha, Jalahalli M AU - Siddesha JM AD - Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, United States; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States. FAU - Valente, Anthony J AU - Valente AJ AD - Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, United States. FAU - Yoshida, Tadashi AU - Yoshida T AD - Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States. FAU - Sakamuri, Siva S V P AU - Sakamuri SS AD - Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States. FAU - Delafontaine, Patrice AU - Delafontaine P AD - Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States. FAU - Iba, Hideo AU - Iba H AD - Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan. FAU - Noda, Makoto AU - Noda M AD - Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan. FAU - Chandrasekar, Bysani AU - Chandrasekar B AD - Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, United States; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States. Electronic address: bchandra@tulane.edu. LA - eng GR - R01 HL070241/HL/NHLBI NIH HHS/United States GR - I01 BX000246/BX/BLRD VA/United States GR - HL-70241/HL/NHLBI NIH HHS/United States GR - R01 HL080682/HL/NHLBI NIH HHS/United States GR - P30 GM103337/GM/NIGMS NIH HHS/United States GR - HL-86787/HL/NHLBI NIH HHS/United States GR - HL-80682/HL/NHLBI NIH HHS/United States GR - R01 HL086787/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140119 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (3' Untranslated Regions) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (GPI-Linked Proteins) RN - 0 (MIRN21 microRNA, mouse) RN - 0 (Membrane Proteins) RN - 0 (MicroRNAs) RN - 0 (Phosphoproteins) RN - 0 (Reck protein, mouse) RN - 0 (STAT3 Transcription Factor) RN - 0 (Spry1 protein, mouse) RN - 0 (Stat3 protein, mouse) RN - 0 (Transcription Factor AP-1) RN - 11128-99-7 (Angiotensin II) RN - 25167-62-8 (Docosahexaenoic Acids) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, mouse) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) SB - IM MH - 3' Untranslated Regions MH - Adaptor Proteins, Signal Transducing/metabolism MH - Angiotensin II/*pharmacology MH - Animals MH - Cell Movement/drug effects MH - Cells, Cultured MH - Docosahexaenoic Acids/*pharmacology MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Fibroblasts/cytology/*drug effects/metabolism MH - GPI-Linked Proteins/antagonists & inhibitors/genetics/*metabolism MH - Male MH - Matrix Metalloproteinase 2/metabolism MH - Membrane Proteins/metabolism MH - Mice MH - Mice, Inbred C57BL MH - MicroRNAs/genetics/metabolism MH - PTEN Phosphohydrolase/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation/drug effects MH - Promoter Regions, Genetic MH - STAT3 Transcription Factor/metabolism MH - Transcription Factor AP-1/metabolism PMC - PMC3951845 MID - NIHMS558147 OTO - NOTNLM OT - Fibrosis OT - MicroRNA OT - PTEN OT - RECK OT - SPRY1 OT - omega-3 lipids COIS- Conflict of Interest: None. EDAT- 2014/01/23 06:00 MHDA- 2014/11/05 06:00 PMCR- 2015/05/01 CRDT- 2014/01/23 06:00 PHST- 2013/12/24 00:00 [received] PHST- 2014/01/08 00:00 [accepted] PHST- 2014/01/23 06:00 [entrez] PHST- 2014/01/23 06:00 [pubmed] PHST- 2014/11/05 06:00 [medline] PHST- 2015/05/01 00:00 [pmc-release] AID - S0898-6568(14)00016-3 [pii] AID - 10.1016/j.cellsig.2014.01.005 [doi] PST - ppublish SO - Cell Signal. 2014 May;26(5):933-41. doi: 10.1016/j.cellsig.2014.01.005. Epub 2014 Jan 19.