Deficiency of miR-409-3p improves myocardial neovascularization and function through modulation of DNAJB9/p38 MAPK signaling.

Autor:	Bestepe F; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Fritsche C; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Lakhotiya K; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Niosi CE; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Ghanem GF; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Martin GL; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Pal-Ghosh R; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Becker-Greene D; Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Weston J; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Hollan I; Department of Health Sciences, Norwegian University of Science and Technology, Gjøvik, Norway., Risnes I; Department of Cardiac Surgery, LHL Hospital Gardermoen, Jessheim, Norway., Rynning SE; Department of Heart Diseases, Haukeland University Hospital, Bergen, Norway., Solheim LH; HMN Lan & Helseplattformen, Trondheim, Norway., Feinberg MW; Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Blanton RM; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA., Icli B; Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 May 20; Vol. 32, pp. 995-1009. Date of Electronic Publication: 2023 May 20 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.05.021
Abstrakt:	Angiogenesis is critical for tissue repair following myocardial infarction (MI), which is exacerbated under insulin resistance or diabetes. MicroRNAs are regulators of angiogenesis. We examined the metabolic regulation of miR-409-3p in post-infarct angiogenesis. miR-409-3p was increased in patients with acute coronary syndrome (ACS) and in a mouse model of acute MI. In endothelial cells (ECs), miR-409-3p was induced by palmitate, while vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) decreased its expression. Overexpression of miR-409-3p decreased EC proliferation and migration in the presence of palmitate, whereas inhibition had the opposite effects. RNA sequencing (RNA-seq) profiling in ECs identified DNAJ homolog subfamily B member 9 (DNAJB9) as a target of miR-409-3p. Overexpression of miR-409-3p decreased DNAJB9 mRNA and protein expression by 47% and 31% respectively, while enriching DNAJB9 mRNA by 1.9-fold after Argonaute2 microribonucleoprotein immunoprecipitation. These effects were mediated through p38 mitogen-activated protein kinase (MAPK). Ischemia-reperfusion (I/R) injury in EC-specific miR-409-3p knockout (KO) mice (miR-409 ECKO ) fed a high-fat, high-sucrose diet increased isolectin B4 (53.3%), CD31 (56%), and DNAJB9 (41.5%). The left ventricular ejection fraction (EF) was improved by 28%, and the infarct area was decreased by 33.8% in miR-409 ECKO compared with control mice. These findings support an important role of miR-409-3p in the angiogenic EC response to myocardial ischemia. Competing Interests: The authors have declared that no conflicts of interest exist with this work. (© 2023 The Authors.)
Databáze:	MEDLINE
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