title: Co-treatment with conjugated linoleic acid and nitrite protects against myocardial infarction.
abstract: According to the CDC, the most common type of heart disease is coronary artery disease, which commonly leads to myocardial infarction (MI). Therapeutic approaches to lessen the resulting cardiovascular injury associated with MI are limited. Recently, MicroRNAs (miRNAs) have been shown to act as negative regulators of gene expression by inhibiting mRNA translation and/or stimulating mRNA degradation. A single miRNA can modulate physiological or disease phenotypes by regulating whole functional systems. Importantly, miRNAs can regulate cardiac function, thereby modulating heart muscle contraction, heart growth and morphogenesis. MicroRNA-499 (miRNA-499) is a cardiac-specific miRNA that when elevated causes cardiomyocyte hypertrophy, in turn preventing cardiac dysfunction during MI. Previous studies revealed that combination treatment with conjugated linoleic acid (cLA) and nitrite preserved cardiovascular function in mice. Therefore, it was hypothesized that cLA and nitrite may regulate miRNA-499, thus providing cardiac protection during MI. To test this hypothesis, 12-week old mice were treated with cLA (10 mg/kg/d-via osmotic mini-pump) or cLA and nitrite (50 ppm-drinking water) 3 days prior to MI (ligation of the left anterior descending artery). Echocardiography and pressure-volume (PV)-loop analysis revealed that cLA and nitrite-treated MI mice had improved heart function (10 days following MI) compared to untreated MI mice. Treatment with cLA and nitrite significantly induced levels of miRNA-499 compared to untreated MI mice. In addition, treatment with cLA and nitrite abolished MI-induced protein expression of p53 and dynamin-related protein-1 (DRP-1). Moreover, the antioxidant enzyme expression of heme oxygenase-1 (HO-1) was elevated in MI mice treated with cLA and nitrite compared to untreated MI mice. Confocal imaging on heart tissue confirmed expression the levels of HO-1 and p53. Taken together, these results suggest that therapeutic treatment with cLA and nitrite may provide significant protection during MI through regulation of both cardiac specific miRNA-499 and upregulation of phase 2 antioxidant enzyme expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, KY 40202, United States ; Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Natia
authors.initials: N
authors.lastname: Qipshidze-Kelm
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Kellianne M
authors.initials: KM
authors.lastname: Piell
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Solinger
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, KY 40202, United States ; Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Marsha P
authors.initials: MP
authors.lastname: Cole
mesh_terms: D000818:Animals; D034281:Dynamins / Q000378:metabolism; D004452:Echocardiography; D006321:Heart / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006439:Hemodynamics; D044243:Linoleic Acids, Conjugated / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009573:Nitrites / Q000627:therapeutic use*; D020011:Protective Agents / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D044243:Linoleic Acids, Conjugated; C573190:MIRN499 microRNA, mouse; D035683:MicroRNAs; D009573:Nitrites; D020011:Protective Agents; D016159:Tumor Suppressor Protein p53; D051547:Heme Oxygenase-1; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Apoptosis; Conjugated linoleic acid; Drp-1; Myocardial infarction; Nitrite