Pulinilkunnil Thomas, Abrahani Ashraf, Varghese Jospy, Chan Nathan, Tang Irvin, Ghosh Sanjoy, Kulpa Jerze, Allard Michael, Brownsey Roger, Rodrigues Brian
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, Canada V6T 1Z3.
J Mol Cell Cardiol. 2003 Sep;35(9):1093-103. doi: 10.1016/s0022-2828(03)00205-0.
During diabetes, impaired glucose transport and utilization by the heart switches energy production to exclusive beta-oxidation of fatty acid (FA). In the current study, we examined the contribution of cardiac lipoprotein lipase (LPL) towards providing FA to the diabetic heart. Streptozotocin (STZ) caused an augmentation of LPL activity at the coronary lumen, an effect duplicated by diazoxide (DZ). With DZ, the amplification of LPL at the coronary luminal surface was determined to be exceptionally rapid. Interestingly, unlike DZ, the capability of hearts from STZ animals to maintain this amplified LPL activity was sustained in vitro. This increased enzyme in the hyperglycemic heart is likely unrelated to an increase in the number of capillary endothelial LPL-binding sites. Our data imply that binding sites for LPL in the control rat heart are only partly occupied by the enzyme and diabetes rapidly initiates filling of all of these sites. Phloridzin treatment of STZ animals normalized plasma glucose with no effect on luminal LPL suggesting that the effects of diabetes on LPL are also largely independent of changes in blood glucose. Both 2 and 8 U of insulin normalized plasma glucose in DZ-treated animals but only 8 U reversed DZ-induced augmentation of cardiac luminal LPL. Our data suggest that impaired intracellular glucose utilization allows rapid vectorial transfer of LPL to unoccupied binding sites to supply the diabetic heart with excess FA. The persistence of increased coronary luminal LPL even in a setting of normoglycemia may provide excessive FA to the diabetic heart with deleterious consequences over the long term.
在糖尿病期间，心脏对葡萄糖的转运和利用受损，能量产生转而完全依赖脂肪酸（FA）的β氧化。在本研究中，我们考察了心脏脂蛋白脂肪酶（LPL）对为糖尿病心脏提供FA的作用。链脲佐菌素（STZ）导致冠状动脉腔处LPL活性增强，二氮嗪（DZ）也有同样的作用。使用DZ后，冠状动脉腔表面LPL的增强作用被确定非常迅速。有趣的是，与DZ不同，STZ处理动物的心脏在体外仍能维持这种增强的LPL活性。高血糖心脏中这种酶的增加可能与毛细血管内皮LPL结合位点数量的增加无关。我们的数据表明，正常大鼠心脏中LPL的结合位点只有部分被该酶占据，而糖尿病会迅速使所有这些位点被填满。用根皮苷处理STZ动物可使血糖正常化，但对腔内LPL没有影响，这表明糖尿病对LPL的影响在很大程度上也与血糖变化无关。2单位和8单位胰岛素均可使DZ处理动物的血糖正常化，但只有8单位胰岛素能逆转DZ诱导的心脏腔内LPL增强。我们的数据表明，细胞内葡萄糖利用受损使得LPL快速向未占据的结合位点进行矢量转移，从而为糖尿病心脏提供过量的FA。即使在血糖正常的情况下，冠状动脉腔内LPL持续增加，可能会长期为糖尿病心脏提供过量的FA，从而产生有害后果。
