Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice.
Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice.
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DOI：
10.1152/ajpheart.00454.2012
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发表时间：
2013-05
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通讯作者：
Ayako Takahashi;M. Asakura;S. Ito;Kyung-duk Min;Kazuhiro Shindo;Yi Yan;Y. Liao;S. Yamazaki;S. Sanada;Y. Asano;H. Ishibashi-Ueda;S. Takashima;T. Minamino;H. Asanuma;N. Mochizuki;M. Kitakaze
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作者：
Ayako Takahashi;M. Asakura;S. Ito;Kyung-duk Min;Kazuhiro Shindo;Yi Yan;Y. Liao;S. Yamazaki;S. Sanada;Y. Asano;H. Ishibashi-Ueda;S. Takashima;T. Minamino;H. Asanuma;N. Mochizuki;M. Kitakaze
胰岛素激素，包括胰升糖素样肽-1(GLP-1)，是糖尿病(DM)治疗的靶点，与心脏保护有关。在体内，随着二肽基肽酶IV(DPP-IV)抑制增加血浆GLP-1水平，我们研究了DPP-IV抑制剂维达格列汀在小鼠心力衰竭(HF)模型中的心脏保护作用。我们建立了C57BL/6J小鼠的横动脉收缩(TAC)模型，模拟压力负荷性心肌肥厚和心力衰竭。TAC或假手术组小鼠分别给予或不给予维格列汀治疗。腹膜内葡萄糖耐量试验显示，TAC组小鼠的血糖水平高于假手术组，给予维格列汀后，这两组小鼠的血糖水平都有所改善。维达格列汀可提高TAC小鼠的血浆GLP-1水平，并改善TAC诱导的左心室增大和功能障碍。组织学、基因和蛋白表达分析表明，维达格列汀可减轻TAC小鼠的心肌细胞凋亡和纤维化，并提高第28天的存活率(使用维达格列汀的TAC为67.5%；不使用维达格列汀的TAC为41.5%；P<；0.05)。Vildagliptin通过改善受损的糖耐量和增加GLP-1水平，改善了TAC小鼠的心功能障碍和总存活率。DPP-IV抑制剂是治疗合并或不合并糖尿病的心力衰竭患者的候选药物。
Incretin hormones, including glucagon-like peptide-1 (GLP-1), a target for diabetes mellitus (DM) treatment, are associated with cardioprotection. As dipeptidyl-peptidase IV (DPP-IV) inhibition increases plasma GLP-1 levels in vivo, we investigated the cardioprotective effects of the DPP-IV inhibitor vildagliptin in a murine heart failure (HF) model. We induced transverse aortic constriction (TAC) in C57BL/6J mice, simulating pressure-overloaded cardiac hypertrophy and HF. TAC or sham-operated mice were treated with or without vildagliptin. An intraperitoneal glucose tolerance test revealed that blood glucose levels were higher in the TAC than in sham-operated mice, and these levels improved with vildagliptin administration in both groups. Vildagliptin increased plasma GLP-1 levels in the TAC mice and ameliorated TAC-induced left ventricular enlargement and dysfunction. Vildagliptin palliated both myocardial apoptosis and fibrosis in TAC mice, demonstrated by histological, gene and protein expression analyses, and improved survival rate on day 28 (TAC with vildagliptin, 67.5%; TAC without vildagliptin, 41.5%; P < 0.05). Vildagliptin improved cardiac dysfunction and overall survival in the TAC mice, both by improving impaired glucose tolerance and by increasing GLP-1 levels. DPP-IV inhibitors represent a candidate treatment for HF patients with or without DM.