title: Cardiac hypertrophy caused by peroxisome proliferator- activated receptor-gamma agonist treatment occurs independently of changes in myocardial insulin signaling.
abstract: Peroxisome proliferator-activated receptor (PPAR)-gamma ligands are insulin sensitizers, widely used in the treatment of type 2 diabetes. A consistent observation in preclinical species is the development of cardiac hypertrophy after short-term treatment with these agents. The mechanisms for this hypertrophy are incompletely understood. Given the important role of insulin signaling in the regulation of myocardial size, we tested the hypothesis that augmentation of myocardial insulin signaling may play a role in PPAR-gamma ligand-induced cardiac hypertrophy. We treated mice with cardiomyocyte-restricted knockout of insulin receptors (CIRKO) and littermate controls (wild type) with 2-(2-(4-phenoxy-2-propylphenoxy) ethyl) indole-5-acetic acid (COOH), which is a non-thiazolidinedione PPAR-gamma agonist for 2 wk. Two weeks of COOH treatment increased heart weights by 22% in CIRKO mice and 16% in wild type, and induced similar fold increase in the expression of hypertrophic markers such as alpha-skeletal actin, brain natriuretic peptide, and atrial natriuretic peptide in CIRKO and wild-type (WT) hearts. COOH treatment increased plasma volume by 10% in COOH-treated WT and CIRKO mice but did not increase systolic or diastolic blood pressure. Echocardiographic analysis was also consistent with volume overload, as evidenced by increased left ventricular diastolic diameters and cardiac output in COOH-treated CIRKO and WT mice. These data indicate that cardiac hypertrophy after PPAR-gamma agonist treatment can occur in the absence of myocardial insulin signaling and is likely secondary to the hemodynamic consequences of plasma volume expansion.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, Program in Human Molecular Biology and Genetics, 15 North 2030 East, Salt Lake City, UT 84112, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sena
authors.forename: Isaac R
authors.initials: IR
authors.lastname: Rasmussen
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Alfred P
authors.initials: AP
authors.lastname: McQueen
authors.forename: Heather A
authors.initials: HA
authors.lastname: Theobald
authors.forename: Nicole
authors.initials: N
authors.lastname: Wilde
authors.forename: Renata Oliveira
authors.initials: RO
authors.lastname: Pereira
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D004452:Echocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006334:Heart Function Tests; D006400:Hematocrit; D007211:Indoles / Q000494:pharmacology / Q000633:toxicity; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D010953:Plasma Volume / Q000187:drug effects; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology