Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Mohali, 160062, Punjab, India.
Mol Cell Biochem. 2019 Jan;451(1-2):69-78. doi: 10.1007/s11010-018-3394-9. Epub 2018 Jul 3.
Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50 mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1 mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease-activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFκB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis.
慢性糖尿病与高血压和冠状动脉疾病无关的心室功能障碍有关。这种情况被称为糖尿病心肌病（DCM）。目前尚无治疗糖尿病心肌病的有效方法。最近的研究报告称，糖尿病患者的循环凝血酶水平升高，导致血液高凝。凝血酶诱导炎症和纤维化，并增强体外心肌细胞的生长和收缩性。在这项研究中，我们研究了直接凝血酶抑制剂Argatroban对链脲佐菌素诱导的 1 型糖尿病的 DCM 的影响。糖尿病通过单次腹腔注射链脲佐菌素（STZ；50mg/kg）诱导雄性 Sprague-Dawley 大鼠。糖尿病诱导 4 周后，动物用 Argatroban（0.3 和 1mg/kg，腹腔注射，每日）治疗 4 周。评估 Argatroban 对与糖尿病相关的心脏功能障碍、结构改变和蛋白表达的影响。STZ 诱导的糖尿病大鼠表现出左心室功能明显下降。Argatroban 治疗 4 周可显著改善心室功能，而不影响心率。此外，它还通过减少纤维化、肥大和细胞凋亡来保护心脏免受糖尿病引起的结构变化。心脏功能的改善和结构变化与左心室凝血酶受体（也称为蛋白酶激活受体-1 或 PAR1）、p-AKT（ser-473）、p-50 NFκB 和 caspase-3 蛋白的表达显著降低有关。这项研究表明 Argatroban 通过改善 STZ 诱导的 DCM 中的心脏功能和结构变化具有有益作用。这些作用可能归因于通过减少心脏炎症、纤维化和细胞凋亡。
