Departament of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
Ciber Enfermedades Respiratorias (Ciberes), Madrid, Spain.
PLoS One. 2019 Jan 28;14(1):e0211281. doi: 10.1371/journal.pone.0211281. eCollection 2019.
Diabetes is a very strong predictor of chronic systemic vascular diseases and acute cardiovascular events. Recently, associations between metabolic disorders and pulmonary hypertension have also been reported in both humans and animal models. In order to get some further insight into the relationship of pulmonary hypertension with obesity, insulin resistance and hyperglycemia, herein we have used the Zucker diabetic fatty rats (ZDF/clr-lepr fa) at 20 weeks fed a standard diet and compared to their lean Zucker littermates (ZL). ZDF rats were obese, had elevated plasma glucose levels and insulin resistance, i.e. a clinically relevant model of type 2 diabetes. They presented elevated systolic, diastolic and mean pulmonary arterial pressures and a parallel increase in the Fulton index. Systemic arterial pressures were also increased but the left ventricle plus septum weight was similar in both groups and the heart rate was reduced. Wall media thickening was observed in the small pulmonary arteries from the ZDF rats. Isolated pulmonary arteries mounted in a wire myograph showed similar vasoconstrictor responses to phenylephrine and 5-HT and similar responses to the endothelium-dependent vasodilator acetylcholine. However, the iNOS inhibitor 1400W enhanced the vasoconstrictor responses in ZDF but not in ZL rats. The protein expression of eNOS and iNOS was not significantly different in the lungs of the two groups. The lung expression of Bmpr2 mRNA was downregulated. However, the mRNA expression of Kcna5, Kcnk3, Kcnq1, Kcnq4 or Kcnq5, which encode for the potassium channels Kv1.5, TASK-1, Kv7.1, Kv7.4 and Kv7.5, respectively, was similar in ZL and ZDF rats. In conclusion, ZDF rats show increased pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arterial medial thickening and downregulated lung Bmpr2 despite leptin resistance. These changes were mild but are consistent with the view that diabetes is a risk factor for pulmonary hypertension.
糖尿病是慢性全身性血管疾病和急性心血管事件的一个非常强的预测因子。最近，在人类和动物模型中也报道了代谢紊乱与肺动脉高压之间的关联。为了更深入地了解肺动脉高压与肥胖、胰岛素抵抗和高血糖之间的关系，我们在此使用 20 周龄的 Zucker 糖尿病肥胖大鼠（ZDF/clr-lepr fa）喂食标准饮食，并与它们的 lean Zucker 同窝仔鼠（ZL）进行比较。ZDF 大鼠肥胖，血糖水平升高，存在胰岛素抵抗，即 2 型糖尿病的一种临床相关模型。它们表现出收缩压、舒张压和平均肺动脉压升高，以及 Fulton 指数的平行升高。系统性动脉压也升高，但两组的左心室加室间隔重量相似，心率降低。从小的肺动脉中观察到 ZDF 大鼠的壁媒体增厚。在置于金属丝肌动描记器中的分离肺动脉中，观察到对苯肾上腺素和 5-HT 的相似血管收缩反应，以及对内皮依赖性血管扩张剂乙酰胆碱的相似反应。然而，iNOS 抑制剂 1400W 增强了 ZDF 大鼠而不是 ZL 大鼠的血管收缩反应。两组肺组织中 eNOS 和 iNOS 的蛋白表达没有显著差异。Bmpr2 mRNA 在两组肺中的表达下调。然而，编码 Kv1.5、TASK-1、Kv7.1、Kv7.4 和 Kv7.5 的钾通道 Kv1.5、TASK-1、Kv7.1、Kv7.4 和 Kv7.5 的 Kcna5、Kcnk3、Kcnq1、Kcnq4 或 Kcnq5 的 mRNA 表达在 ZL 和 ZDF 大鼠中相似。总之，尽管存在瘦素抵抗，ZDF 大鼠仍表现出肺动脉压升高、右心室肥厚、肺动脉中层增厚和肺 Bmpr2 下调。这些变化虽然轻微，但与糖尿病是肺动脉高压的一个危险因素的观点一致。
