title: Activation of Peroxisome Proliferator-activated Receptor γ Prevents Development of Heart Failure With Preserved Ejection Fraction; Inhibition of Wnt-β-catenin Signaling as a Possible Mechanism.
abstract: Left ventricular (LV) fibrosis plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). We investigated whether chronic peroxisome proliferator-activated receptor gamma agonism with pioglitazone can prevent the development of HFpEF. We also evaluated the role of Wnt-β-catenin signaling in the development of HFpEF, and its relationship to peroxisome proliferator-activated receptor gamma signaling. Dahl salt-sensitive rats placed on an 8% NaCl diet from age 6 weeks were used as HFpEF model. Rats placed on 0.3% NaCl diet served as controls (n = 7). HFpEF model rats were randomized to no treatment (n = 7) or treatment with pioglitazone (2.5 mg/kg per day, n = 7) at age 13 weeks. Pioglitazone administration from age 13 to 21 weeks attenuated the development of LV fibrosis and stiffening (both P < 0.05), and subsequently prevented the development of HFpEF. In the untreated HFpEF model, Wnt1, 2, 10b messenger RNA and β-catenin protein expression levels in the left ventricle increased in the heart failure stage, along with the increase in type I collagen messenger RNA expression levels. Administration of pioglitazone attenuated the activation of Wnt-β-catenin signaling. Our results show that pioglitazone prevented the development of LV fibrosis and HFpEF in a rat model, at least partly due to attenuated Wnt-β-catenin signaling.
authors.affiliation: *Department of Medicine, Cardiology, University of Mississippi Medical Center, Jackson, MS; and †Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Uchino
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishigami
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hall
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary; D013318:Stroke Volume / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D051154:Wnt2 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; C495268:Ctnnb1 protein, rat; D047495:PPAR gamma; C000613696:PPAR gamma, rat; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D045162:Thiazolidinediones; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495245:Wnt1 protein, rat; C501228:Wnt10b protein, rat; D051154:Wnt2 Protein; D051176:beta Catenin; D000077205:Pioglitazone