硝酸甘油扩张血管的原因在于它能够激活有“动力工厂”之称的线粒体
据奥地利新闻社报道，奥地利格拉茨大学等机构的研究人员日前发表报告说，他们发现了硝酸甘油扩张血管的作用机理，有望在未来大幅提高这类血管扩张药物的疗效。
硝酸甘油等硝酸盐类血管扩张药物目前主要用来治疗心绞痛等症状，但长期使用会因患者产生耐受力而失效。
研究人员发现，硝酸甘油扩张血管的功能在于，它激活了有细胞“动力工厂”之称的线粒体，这其中发挥作用的是一种名为“乙醛脱氢酶2”的物质，并且硝酸甘油在激活线粒体的同时又反过来起到抑制“乙醛脱氢酶2”活性的作用。
基于这一发现，研究人员借助晶体结构和质谱法，再现了“乙醛脱氢酶2”与硝酸甘油反应的三维结构。这一成果让研究人员能深入观察和了解“乙醛脱氢酶2”对硝酸甘油的作用机制，从而能有针对性地调整药品结构，改善功效。
Vascular Bioactivation of Nitroglycerin Is Catalyzed by Cytosolic Aldehyde Dehydrogenase-2
Matteo Beretta, Gerald Wölkart, Michaela Schernthaner et al.
Rationale: According to general view, aldehyde dehydrogenase-2 (ALDH2) catalyzes the high-affinity pathway of vascular nitroglycerin (GTN) bioactivation in smooth muscle mitochondria. Despite having wide implications to GTN pharmacology and raising many questions that are still unresolved, mitochondrial bioactivation of GTN in blood vessels is still lacking experimental support.
Objective: In the present study, we investigated whether bioactivation of GTN is affected by the subcellular localization of ALDH2 using immortalized ALDH2-deficient aortic smooth muscle cells and mouse aortas with selective overexpression of the enzyme in either cytosol or mitochondria.
Methods and Results: Quantitative Western blotting revealed that ALDH2 is mainly cytosolic in mouse aorta and human coronary arteries, with only approximately 15% (mouse) and approximately 5% (human) of the enzyme being localized in mitochondria. Infection of ALDH2-deficient aortic smooth muscle cells or isolated aortas with adenovirus containing ALDH2 cDNA with or without the mitochondrial signal peptide sequence led to selective expression of the protein in mitochondria and cytosol, respectively. Cytosolic overexpression of ALDH2 restored GTN-induced relaxation and GTN denitration to wild-type levels, whereas overexpression in mitochondria (6-fold vs wild-type) had no effect on relaxation. Overexpression of ALDH2 in the cytosol of ALDH2-deficient aortic smooth muscle cells led to a significant increase in GTN denitration and cyclic GMP accumulation, whereas mitochondrial overexpression had no effect.
Conclusions: The data indicate that vascular bioactivation of GTN is catalyzed by cytosolic ALDH2. Mitochondrial GTN metabolism may contribute to oxidative stress-related adverse effects of nitrate therapy and the development of nitrate tolerance.
文献链接：Vascular Bioactivation of Nitroglycerin Is Catalyzed by Cytosolic Aldehyde Dehydrogenase-2
