title: Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats.
abstract: Human chymase activates not only angiotensin II but also transforming growth factor-beta, a major stimulator of myocardial fibrosis, while rat chymase activates transforming growth factor-beta, but not angiotensin II. To clarify the role of chymase-dependent transforming growth factor-beta activation, we evaluated whether chymase inhibition prevents cardiac fibrosis and cardiac dysfunction after myocardial infarction in rats. Myocardial infarction was induced by ligation of the left anterior descending coronary artery. One day after the ligation, rats were randomized into 2 groups: 1) a chymase-treated group that received 10 mg/kg per day of the chymase inhibitor NK3201 orally for 4 weeks; and 2) a vehicle group of non-treated rats with myocardial infarction. We also included a control group who underwent sham-operation and no treatment. Four weeks after ligation, echocardiography revealed that chymase inhibitor treatment reduced the akinetic area and increased fractional area change but did not significantly change left ventricular end-diastolic area. Chymase inhibition significantly reduced left ventricular end-diastolic pressure, increased the maximal end-systolic pressure-volume relationship and decreased the time constant of left ventricular relaxation. Chymase activity in the non-infarcted myocardium was significantly increased in the vehicle group, but it was significantly reduced by chymase inhibitor treatment. The fibrotic area in the cardiac tissues and the mRNA levels of collagen I and collagen III were also significantly lower in the chymase inhibitor-treated group than in the vehicle group. Therefore, the pathway forming chymase-dependent transforming growth factor-beta may play an important role in myocardial fibrosis and cardiac dysfunction rather than left ventricular dilatation after myocardial infarction.
authors.affiliation: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kanemitsu
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneyoshi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishina
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ikeda
authors.forename: Masashi
authors.initials: M
authors.lastname: Komeda
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D053818:Chymases; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis; D004452:Echocardiography; D005355:Fibrosis; D006331:Heart Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000081:Acetamides; D024042:Collagen Type I; D024061:Collagen Type III; C437945:NK3201; D011480:Protease Inhibitors; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D012697:Serine Endopeptidases; D053818:Chymases