title: Pioglitazone increases PGC1-α signaling within chronically ischemic myocardium.
abstract: The peroxisome proliferator-activated receptor (PPAR)-γ drug pioglitazone (PIO) has been shown to protect tissue against oxidant stress. In a swine model of chronic myocardial ischemia, we tested whether PIO increases PGC1-α signaling and the expression of mitochondrial antioxidant peptides. Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8 weeks, diet was supplemented with either PIO (3 mg/kg) or placebo for 4 weeks. Regional myocardial function and blood flow were determined at the time of the terminal study. PGC1-α expression was quantified from nuclear membranes by gels and respiration, oxidant stress markers and proteomics by iTRAQ were determined from isolated mitochondria. In the chronically ischemic LAD region, wall thickening from the PIO and control groups was 42 ± 6 and 45 ± 5 %, respectively (NS) with no intergroup differences in basal blood flow (0.72 ± 0.04 versus 0.74 ± 0.04 ml/min g, respectively; NS). In the PIO group, the expression of nuclear bound PGC1-α was higher (11.3 ± 2.6 versus 4.4 ± 1.4 AU; P < 0.05) and the content of mitochondrial antioxidant peptides including superoxide dismutase 2, aldose reductase, glutathione S-transferase and thioredoxin reductase were greater than controls. Although isolated mitochondria from the PIO group showed lower state 3 respiration (102 ± 13 versus 161 ± 22 nmol/min mg; P < 0.05), no differences in oxidant stress were noted by protein carbonyl (1.7 ± 0.7 versus 1.1 ± 0.1 nmol/mg). Chronic pioglitazone does not reduce regional myocardial blood flow or function in a swine model of chronic myocardial ischemia, but may have an important role in increasing expression of antioxidant proteins through PGC1-α signaling.
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.|Cardiology and Cardiothoracic Surgery Sections, Department of Nutrition, VA Medical Center, Minneapolis, USA.|Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN, 55108, USA.
authors.forename: Tammy A
authors.initials: TA
authors.lastname: Butterick
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hocum Stone
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.|Cardiology and Cardiothoracic Surgery Sections, Department of Nutrition, VA Medical Center, Minneapolis, USA.
authors.forename: Cayla
authors.initials: C
authors.lastname: Duffy
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Holley
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.
authors.forename: Jesús A
authors.initials: JA
authors.lastname: Cabrera
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Crampton
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Ward
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA.|Department of Surgery, University of Minnesota, Minneapolis, USA.
authors.forename: Rosemary F
authors.initials: RF
authors.lastname: Kelly
authors.affiliation: Cardiology and Cardiothoracic Surgery Sections, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA. mcfal001@umn.edu.|Department of Surgery, University of Minnesota, Minneapolis, USA. mcfal001@umn.edu.
authors.forename: Edward O
authors.initials: EO
authors.lastname: McFalls
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D034421:Sus scrofa; D013552:Swine; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Antioxidants; Chronic myocardial ischemia; Glitazones; Mitochondria; PGC1-alpha; Proteomics