Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Cardiac Services, Maine Medical Center, Portland, Maine.
J Card Fail. 2017 Dec;23(12):887-899. doi: 10.1016/j.cardfail.2017.08.456. Epub 2017 Sep 4.
Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular morbidity and mortality compared to their nondiabetic counterparts owing to the more frequent development of subsequent heart failure (HF). Neuregulin (NRG)-1β is released from cardiac microvascular endothelial cells and acts as a paracrine factor via the ErbB family of tyrosine kinase receptors expressed in cardiac myocytes to regulate cardiac development and stress responses. Because myocardial NRG-1/ErbB signaling has been documented to be impaired during HF associated with type 1 DM, we examined whether enhancement of NRG-1β signaling via exogenous administration of recombinant NRG-1β could exert beneficial effects against post-MI HF in the type 1 diabetic heart.
Type 1 DM was induced in male Sprague Dawley rats by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 µg/kg) twice per week for 7 weeks, starting 2 weeks before experimental MI. Residual left ventricular function was significantly greater in the NRG-1β-treated STZ-diabetic MI group compared with the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. NRG-1β treatment of STZ-diabetic MI rats was associated with reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes.
These results suggest that recombinant NRG-1β may be a promising therapeutic for HF post-MI in the setting of type 1 DM.
与非糖尿病患者相比，1 型糖尿病（DM）患者幸存心肌梗死（MI）后心血管发病率和死亡率显著更高，这是由于随后心力衰竭（HF）的发生率更高。神经调节蛋白（NRG）-1β 从心脏微血管内皮细胞释放，并通过心肌细胞中表达的 ErbB 家族酪氨酸激酶受体作为旁分泌因子发挥作用，以调节心脏发育和应激反应。由于已经证明在与 1 型 DM 相关的 HF 期间心肌 NRG-1/ErbB 信号受损，我们研究了通过外源性给予重组 NRG-1β 增强 NRG-1β 信号是否可以对 1 型糖尿病心脏的 MI 后 HF 发挥有益作用。
通过单次注射链脲佐菌素（STZ）（65mg/kg）诱导雄性 Sprague Dawley 大鼠产生 1 型 DM。在诱导 1 型 DM 2 周后，大鼠进行左冠状动脉结扎以诱导 MI。STZ 糖尿病大鼠在实验性 MI 前 2 周开始每周接受两次盐水或 NRG-1β（100μg/kg）治疗，共 7 周。通过高分辨率超声心动图评估，在 MI 后 5 周时，NRG-1β 治疗的 STZ 糖尿病 MI 组的左心室功能残余明显大于载体治疗的 STZ 糖尿病 MI 组。NRG-1β 治疗 STZ 糖尿病 MI 大鼠与心肌纤维化和细胞凋亡减少以及关键产氧化剂基因表达降低有关。
这些结果表明，重组 NRG-1β 可能是 1 型 DM 后 MI 后 HF 的一种有前途的治疗方法。
