title: Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure.
abstract: Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure.NEW & NOTEWORTHYThe present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaimoto
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ariyoshi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Okawa
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tateishi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Motoki
authors.initials: M
authors.lastname: Uchihashi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Fukai
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and.|Faculty of Health Care, Tenri Health Care University, Nara, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Iwai-Kanai
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and matoba@koto.kpu-m.ac.jp.
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics*; D010710:Phosphates / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D010710:Phosphates; D011743:Pyrimidines; C006253:pirinixic acid; D005947:Glucose
keywords: PPAR-α; energy metabolism; fatty acid oxidation; heart failure