Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University, Beijing, China.
Diabetes. 2014 Aug;63(8):2643-55. doi: 10.2337/db13-1842. Epub 2014 Mar 7.
After diabetes, the heart has a singular reliance on fatty acid (FA) for energy production, which is achieved by increased coronary lipoprotein lipase (LPL) that breaks down circulating triglycerides. Coronary LPL originates from cardiomyocytes, and to translocate to the vascular lumen, the enzyme requires liberation from myocyte surface heparan sulfate proteoglycans (HSPGs), an activity that needs to be sustained after chronic hyperglycemia. We investigated the mechanism by which endothelial cells (EC) and cardiomyocytes operate together to enable continuous translocation of LPL after diabetes. EC were cocultured with myocytes, exposed to high glucose, and uptake of endothelial heparanase into myocytes was determined. Upon uptake, the effect of nuclear entry of heparanase was also investigated. A streptozotocin model of diabetes was used to expand our in vitro observations. In high glucose, EC-derived latent heparanase was taken up by cardiomyocytes by a caveolae-dependent pathway using HSPGs. This latent heparanase was converted into an active form in myocyte lysosomes, entered the nucleus, and upregulated gene expression of matrix metalloproteinase-9. The net effect was increased shedding of HSPGs from the myocyte surface, releasing LPL for its onwards translocation to the coronary lumen. EC-derived heparanase regulates the ability of the cardiomyocyte to send LPL to the coronary lumen. This adaptation, although acutely beneficial, could be catastrophic chronically because excess FA causes lipotoxicity. Inhibiting heparanase function could offer a new strategy for managing cardiomyopathy observed after diabetes.
糖尿病后，心脏对脂肪酸（FA）产生了特殊的依赖，以产生能量，这是通过增加冠状动脉脂蛋白脂肪酶（LPL）来实现的，LPL 可以分解循环中的甘油三酯。冠状动脉 LPL 来源于心肌细胞，为了向血管腔移位，酶需要从心肌细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）中释放出来，这种活性在慢性高血糖后仍需要维持。我们研究了内皮细胞（EC）和心肌细胞一起运作的机制，以实现糖尿病后 LPL 的持续移位。将 EC 与心肌细胞共培养，使其暴露于高葡萄糖环境中，并测定内皮肝素酶进入心肌细胞的摄取情况。摄取后，还研究了肝素酶进入细胞核的作用。使用链脲佐菌素（STZ）建立糖尿病模型，以扩展我们的体外观察结果。在高葡萄糖环境中，EC 衍生的潜伏型肝素酶通过 HSPGs 依赖小窝蛋白的途径被心肌细胞摄取。这种潜伏型肝素酶在心肌细胞溶酶体中转化为活性形式，进入细胞核，并上调基质金属蛋白酶-9 的基因表达。最终结果是心肌细胞表面 HSPGs 的脱落增加，释放出 LPL，使其进一步向冠状动脉腔移位。EC 衍生的肝素酶调节了心肌细胞将 LPL 输送到冠状动脉腔的能力。这种适应虽然在急性情况下是有益的，但从长期来看可能是灾难性的，因为过量的 FA 会导致脂肪毒性。抑制肝素酶的功能可能为管理糖尿病后观察到的心肌病提供一种新策略。
