Cardiac DPP-4 inhibition by saxagliptin ameliorates isoproterenol-induced myocardial remodeling and cardiac diastolic dysfunction in rats.
Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure.
Nephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Junichi
J
Ikeda
Research Core Function Laboratories, Research Function Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Naoya
N
Kimoto
Nephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Tetsuya
T
Kitayama
Nephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. Electronic address: shunji.kunori@kyowa-kirin.co.jp.
Shunji
S
Kunori
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003971:Diastole; D004151:Dipeptides / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004452:Echocardiography; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D007545:Isoproterenol; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects*
D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D018819:Dipeptidyl Peptidase 4; D007545:Isoproterenol; D000218:Adamantane
Cardiac diastolic dysfunction; Cardiac dipeptidyl peptidase-4; Dipeptidyl peptidase-4 inhibitor; Myocardial remodeling; Saxagliptin