Glucose-6-phosphate dehydrogenase: a novel therapeutic target in cardiovascular diseases.
Glucose-6-phosphate dehydrogenase: a novel therapeutic target in cardiovascular diseases.
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发表时间：
2008-09
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通讯作者：
S. Gupte
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作者：
S. Gupte
与糖尿病、心力衰竭和肺动脉高压相关的血管功能障碍是世界范围内发病率和死亡率的主要原因。尽管血管功能障碍的原因尚不清楚，但糖代谢异常似乎是这些疾病的共同因素。例如，在糖尿病中，葡萄糖-6-磷酸脱氢酶(G6PD)活性增加和NADPH水平升高与内皮和血管功能障碍有关。此外，与正常心脏相比，起搏诱导的心力衰竭患者心肌G6PD表达增加10倍，G6PD活性增加2倍。此外，抑制G6PD可改善慢性缺氧性肺动脉高压。最后，G6PD在介导血管紧张素II诱导的平滑肌肥大和动脉粥样硬化的发展中发挥作用。据了解，G6PD衍生的NADPH是NADPH氧化酶的辅助因子，在糖尿病、心力衰竭和血管紧张素II诱导的平滑肌肥大中，G6PD和G6PD衍生的NADPH可促进超氧阴离子的产生并提高氧化应激，但目前还没有特效药来研究G6PD和G6PD衍生的NADPH在器官功能和人类疾病发展中的作用。这就需要开发新的药物或基因方法来靶向G6PD进行研究和临床应用。该综述讨论了现有研究中的G6PD抑制剂的特异性和副作用。
Vascular dysfunction associated with diabetes, heart failure and pulmonary hypertension is the major cause of morbidity and mortality worldwide. Although the causes of vascular dysfunction remain unclear, altered glucose metabolism appears to be a common factor in these diseases. For example, in diabetes, increased glucose-6-phosphate dehydrogenase (G6PD) activity and elevated NADPH levels are associated with endothelial and vascular dysfunction. Also, there is a 10-fold increase in myocardial G6PD expression and a 2-fold increase in G6PD activity in pacing-induced heart failure compared with normal hearts. In addition, the inhibition of G6PD ameliorates chronic hypoxic pulmonary hypertension. Lastly, G6PD plays a role in mediating angiotensin II-induced hypertrophy of smooth muscle and in the development of atherosclerosis. While it is understood that G6PD-derived NADPH, which is a cofactor for NADPH oxidase, enhances superoxide anion generation and elevates oxidative stress in diabetes, heart failure, and angiotensin II-induced hypertrophy of smooth muscle, there are no specific drugs available to study the role of G6PD and G6PD-derived NADPH in organ function and the development of human diseases. This warrants the development of new drugs or genetic approaches to target G6PD for investigational and clinical use. This review discusses the specificity and side effects of existing investigational G6PD inhibitors.