Department of Experimental Therapeutics, Institute of Pharmacology and Toxicology of National Academy of Medical Sciences of Ukraine, Kiev, Ukraine.
Department of Experimental Therapeutics, Institute of Pharmacology and Toxicology of National Academy of Medical Sciences of Ukraine, Kiev, Ukraine.
Int J Cardiol. 2014 Jun 15;174(2):230-42. doi: 10.1016/j.ijcard.2014.04.117. Epub 2014 Apr 18.
Diabetes mellitus (DM) is a complex syndrome which leads to multiple dysfunctions including vascular disorders. Hyperglycemia is considered to be a key factor responsible for the development of diabetic vascular complications and can mediate their adverse effects through multiple pathways. One of those mechanisms is the activation of protein kinase C (PKC). This important regulatory enzyme is involved in a signal transduction of several vascular functions including vascular smooth muscle contractility. Many studies have shown that hyperglycemia in DM results in oxidative stress. Overproduction of reactive oxygen species (ROS) by different oxidases and the mitochondrial electron transport chain (ETC), advanced glycation end products, polyol pathway flux, and hyperglicemia-induced rising in diacylglycerol (DAG) contribute to the activation of PKC. Activation of endothelial PKC in DM leads to endothelium-dependent vasodilator dysfunction. The main manifestations of this are inhibition of vasodilatation mediated by nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostacyclin, and activation of vasoconstriction mediated by endothelin-1 (ET-1), prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Activated PKC in DM also increases vascular endothelial growth factor (VEGF) expression and activates NADPH oxidases leading to raised ROS production. On the other hand, PKC in DM is involved in enhancement of vascular contractility in an endothelium-independent manner by inactivation of K(+) channels and Ca(2+) sensitization of myofilaments in vascular smooth muscle cells. This shows that PKC is a potential therapeutic target for treating vascular diabetic complications.
糖尿病（DM）是一种复杂的综合征，导致多种功能障碍，包括血管疾病。高血糖被认为是导致糖尿病血管并发症发展的关键因素，并可以通过多种途径介导其不良影响。其中一种机制是蛋白激酶 C（PKC）的激活。这种重要的调节酶参与包括血管平滑肌收缩在内的几种血管功能的信号转导。许多研究表明，糖尿病中的高血糖会导致氧化应激。不同氧化酶和线粒体电子传递链（ETC）、糖基化终产物、多元醇途径通量以及高血糖诱导的二酰基甘油（DAG）升高产生的活性氧物质（ROS）会导致 PKC 的激活。DM 中内皮 PKC 的激活导致内皮依赖性血管舒张功能障碍。其主要表现为抑制一氧化氮（NO）、内皮衍生超极化因子（EDHF）和前列环素介导的血管舒张，激活内皮素-1（ET-1）、前列腺素 E2（PGE2）和血栓素 A2（TXA2）介导的血管收缩。DM 中的激活 PKC 还通过激活 NADPH 氧化酶增加血管内皮生长因子（VEGF）的表达并导致 ROS 产生增加。另一方面，DM 中的 PKC 通过血管平滑肌细胞中 K(+)通道失活和肌球蛋白钙敏化，以非内皮依赖性方式增强血管收缩性。这表明 PKC 是治疗血管性糖尿病并发症的潜在治疗靶点。
