Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Basic Res Cardiol. 2011 Nov;106(6):925-52. doi: 10.1007/s00395-011-0216-6. Epub 2011 Sep 4.
Heart disease and stroke account for 65% of the deaths in people with diabetes mellitus (DM). DM and hyperglycemia cause systemic inflammation, endothelial dysfunction, a hypercoagulable state with impaired fibrinolysis and increased platelet degranulation, and reduced coronary collateral blood flow. DM also interferes with myocardial protection afforded by preconditioning and postconditioning. Newer anti-diabetic agents should not only reduce serum glucose and HbA1c levels, but also improve cardiovascular outcomes. The older sulfonylurea agent, glyburide, abolishes the benefits of ischemic and pharmacologic preconditioning, but newer sulfonylurea agents, such as glimepiride, may not interfere with preconditioning. GLP-1 analogs and sitagliptin, an oral dipeptidyl peptidase IV inhibitor, limit myocardial infarct size in animal models by increasing intracellular cAMP levels and activating protein kinase A, whereas metformin protects the heart by activating AMP-activated protein kinase. Both thiazolidinediones (rosiglitazone and pioglitazone) limit infarct size in animal models. The protective effect of pioglitazone is dependent on downstream activation of cytosolic phospholipase A(2) and cyclooxygenase-2 with subsequent increased production of 15-epi-lipoxin A(4), prostacyclin and 15-d-PGJ(2). We conclude that agents used to treat DM have additional actions that have been shown to affect the ability of the heart to protect itself against ischemia-reperfusion injury in preclinical models. However, the effects of these agents in doses used in the clinical setting to minimize ischemia-reperfusion injury and to affect clinical outcomes in patients with DM have yet to be shown. The clinical implications as well as the mechanisms of protection should be further studied.
心脏病和中风占糖尿病（DM）患者死亡人数的 65%。DM 和高血糖导致全身炎症、内皮功能障碍、高凝状态伴纤溶受损和血小板脱颗粒增加，以及冠状动脉侧支血流减少。DM 还干扰了预处理和后处理提供的心肌保护。新型抗糖尿病药物不仅应降低血清葡萄糖和 HbA1c 水平，还应改善心血管结局。较旧的磺酰脲类药物，如格列本脲，会消除缺血和药物预处理的益处，但较新的磺酰脲类药物，如格列美脲，可能不会干扰预处理。GLP-1 类似物和西他列汀，一种口服二肽基肽酶 IV 抑制剂，通过增加细胞内 cAMP 水平和激活蛋白激酶 A 来限制动物模型中的心肌梗死面积，而二甲双胍通过激活 AMP 激活的蛋白激酶来保护心脏。噻唑烷二酮类药物（罗格列酮和吡格列酮）在动物模型中限制梗死面积。吡格列酮的保护作用依赖于细胞质磷脂酶 A(2)和环氧化酶-2 的下游激活，随后增加 15-epi-脂氧素 A(4)、前列环素和 15-d-PGJ(2)的产生。我们的结论是，用于治疗 DM 的药物具有额外的作用，这些作用已被证明会影响心脏在临床模型中保护自身免受缺血再灌注损伤的能力。然而，这些药物在临床环境中用于最大限度地减少缺血再灌注损伤并影响 DM 患者的临床结局的剂量的作用尚未得到证明。临床意义以及保护机制应进一步研究。
