title: The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice.
abstract: Pirfenidone (5-methyl-1-phenyl-2-[(1)H]-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg(-1) min(-1)) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg(-1) per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-β1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.
authors.affiliation: Department of Internal Medicine and Cardiology, Osaka City University Medical School, Osaka, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamashita
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shiota
authors.forename: Akihisa
authors.initials: A
authors.lastname: Hanatani
authors.forename: Kenei
authors.initials: K
authors.lastname: Shimada
authors.forename: Takashi
authors.initials: T
authors.lastname: Muro
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshiyama
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D005355:Fibrosis / Q000473:pathology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology*; D011728:Pyridones / Q000494:pharmacology*
chemical_list: D011728:Pyridones; D000804:Angiotensin II; C093844:pirfenidone