Amylin Pharmaceuticals Inc, San Diego, CA 92121, USA.
Cardiovasc Diabetol. 2010 Nov 16;9:76. doi: 10.1186/1475-2840-9-76.
Accumulating evidence suggests glucagon-like peptide-1 (GLP-1) exerts cardioprotective effects in animal models of myocardial infarction (MI). We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart failure (CHF) caused by coronary artery ligation.
Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end.
Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression.
Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.
越来越多的证据表明胰高血糖素样肽-1（GLP-1）在心肌梗死（MI）的动物模型中发挥心脏保护作用。我们假设慢性 GLP-1 或 exenatide 类似物 AC3174 的治疗将改善由冠状动脉结扎引起的 MI 后慢性心力衰竭（CHF）大鼠的心脏功能、心脏重塑、胰岛素敏感性和运动能力（EC）。
在 MI 后 2 周，雄性 Sprague-Dawley 大鼠通过皮下输注 GLP-1（2.5 或 25 pmol/kg/min）、AC3174（1.7 或 5 pmol/kg/min）或载体 11 周进行治疗。在治疗期间通过超声心动图评估心脏功能和形态。在研究结束时进行代谢、血液动力学、运动能力和身体成分测量。
与 CHF 大鼠相比，GLP-1 或 AC3174 治疗可显著改善心脏功能，包括左心室（LV）射血分数和舒张末期压。LV 舒张末期和收缩末期容积以及左心房容积减小表明心脏尺寸也得到改善。CHF 大鼠出现空腹高血糖和高胰岛素血症。相比之下，GLP-1 或 AC3174 可使空腹血浆胰岛素和血糖水平正常化。GLP-1 或 AC3174 还显著降低体脂肪和体液量，并改善运动能力和呼吸效率。在研究期间，16 只对照 CHF 大鼠中有 4 只死亡，而 GLP-1 或 AC3174 治疗的 44 只大鼠中只有 1 只死亡。GLP-1 或 AC3174 发挥心脏保护作用的细胞机制似乎与 GLUT1 或 GLUT4 易位或表达的变化无关。
在 CHF 大鼠模型中，慢性 GLP-1 或 AC3174 治疗显示出有希望的心脏保护作用。因此，GLP-1 受体激动剂可能代表治疗 CHF 或与 2 型糖尿病相关的心血管疾病患者的新方法。
