Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Division of Cardiology, Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Thorac Cardiovasc Surg. 2018 Apr;155(4):1661-1669.e4. doi: 10.1016/j.jtcvs.2017.10.085. Epub 2017 Nov 7.
Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats.
Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 μg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology.
Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1β levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness.
Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1β and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.
体循环左向右分流导致肺血管病变，进而导致进行性心肺衰竭和预后不良。本研究旨在探讨合成胰高血糖素样肽 exendin-4 对非糖尿病大鼠肺血管病变消退和心肺功能的影响。
通过皮下注射野百合碱（60mg/kg）诱导肺动脉高压，然后建立腔静脉-主动脉分流。4 周后，连续 3 周每天腹腔内给予 exendin-4（1μg/kg），然后评估心肺功能、肺动脉血管反应性、组织和血液生化以及肺组织学。
exendin-4 显著降低右心室质量和肺动脉压，改善 PH 大鼠的右心室功能和生存率。组织和血液白细胞介素-1β水平降低，而 exendin-4 恢复了肺动脉环磷酸腺苷水平。exendin-4 治疗组肺动脉平滑肌肌球蛋白重链-II 和 α-平滑肌肌动蛋白蛋白水平升高。组织学显示，exendin-4 降低了主肺动脉和腺泡内肺动脉的中膜厚度。
exendin-4 通过其直接的血管活性作用、抗炎作用和血管平滑肌细胞表型调节，改善了血流诱导的 PH 中的肺动脉功能。肺血管病变的减轻进一步增强了右心室功能，降低了总死亡率。这些反应与白细胞介素-1β及其下游信号分子的表达和活性受抑制有关。胰高血糖素样肽类似物在血流诱导的 PH 中可能具有多种治疗潜力。
