Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration.
The omega-3 polyunsaturated fatty acids (ω-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 ω-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.
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.
Jalahalli M
JM
Siddesha
Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, United States.
Anthony J
AJ
Valente
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
Tadashi
T
Yoshida
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
Siva S V P
SS
Sakamuri
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
Patrice
P
Delafontaine
Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan.
Hideo
H
Iba
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan.
Makoto
M
Noda
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.
Bysani
B
Chandrasekar
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D058851:GPI-Linked Proteins; C531950:MIRN21 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D010750:Phosphoproteins; C492025:Reck protein, mouse; D050796:STAT3 Transcription Factor; C425468:Spry1 protein, mouse; C494087:Stat3 protein, mouse; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D004281:Docosahexaenoic Acids; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020778:Matrix Metalloproteinase 2
Fibrosis; MicroRNA; PTEN; RECK; SPRY1; ω−3 lipids