Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Basic Res Cardiol. 2024 Oct;119(5):869-887. doi: 10.1007/s00395-024-01055-z. Epub 2024 May 25.
Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (HO) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased HO acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased HO-mediated coronary vasodilation.
多种常见心血管合并症可导致冠状动脉微血管功能障碍。我们之前在猪身上观察到，糖尿病（DM）、高脂肪饮食（HFD）和慢性肾脏病（CKD）的组合会引起全身炎症、增加氧化应激，并导致冠状动脉内皮功能障碍，通过降低一氧化氮（NO）生物利用度来改变冠状动脉微血管张力的控制，这与循环内皮素（ET）的增加有关。在本研究中，我们测试了以下假设：（1）ROS 清除和（2）ET 受体阻断可改善相同的雌性猪模型中的心肌氧输送。正常猪饲料喂养的健康雌性猪作为对照（正常）。在诱导 DM（链脲佐菌素，3×50mg/kg 静脉内）后 5 个月、高胆固醇血症（HFD）和 CKD（肾栓塞）后，猪被长期植入仪器，并在休息和运动期间进行研究。持续的高血糖、高胆固醇血症和肾功能不全伴有全身炎症和氧化应激。体内 ROS 清除（TEMPOL+MPG）降低了 DM+HFD+CKD 猪的心肌氧输送，提示内源性 ROS 具有血管扩张作用，而在正常猪中则没有影响。在离体小型冠状动脉段中，线描肌动图显示过氧化氢（HO）在 DM+HFD+CKD 猪中具有血管扩张作用，但在正常猪中则没有。DM+HFD+CKD 猪左心室心肌组织中过氧化氢酶活性和神经酰胺产生增加进一步表明，增加的 HO 作为冠状动脉微血管中的血管扩张性 ROS 发挥作用。尽管 DM+HFD+CKD 猪的 ET-1 血浆水平升高，但 ET 阻断在正常或 DM+HFD+CKD 猪中均不影响心肌氧输送。总之，由于暴露于多种合并症 5 个月，NO 生物利用度的丧失部分由 HO 介导的冠状动脉扩张所补偿。
