Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2)
Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2)
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DOI：
10.1096/fj.02-1167fje
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发表时间：
2003-08-01
期刊：
影响因子：
4.8
通讯作者：
Eisenhofer, G
中科院分区：
文献类型：
--
作者：
Bornstein, SR;Yoshida-Hiroi, M;Eisenhofer, G
抗坏血酸（维生素C）是在通过多巴胺β-羟化酶将多巴胺转化为去甲肾上腺素的儿茶酚胺合成中所需的辅因子。缺乏质膜抗坏血酸转运蛋白（SVCT 2）的突变小鼠组织中抗坏血酸水平严重降低，出生后死亡。因此，我们研究了这些小鼠是否可能有受损的儿茶酚胺合成。脑中的儿茶酚胺水平不受SVCT 2缺乏的影响。在心脏中，多巴胺β-羟化酶活性受损的唯一证据是组织多巴胺增加两倍。缺乏对组织儿茶酚胺的影响在肾上腺中最为突出，其中去甲肾上腺素减少50%，肾上腺素减少81%。在超微结构水平上，SVCT 2基因敲除小鼠肾上腺嗜铬细胞显示出儿茶酚胺储存囊泡的耗竭，粗面内质网数量增加，细胞凋亡迹象和糖原储存增加。血浆皮质酮水平降低表明缺乏对肾上腺皮质功能的额外影响。这些数据表明，SVCT 2敲除小鼠中紊乱的儿茶酚胺系统功能主要限于肾上腺髓质，不能解释这些动物的致死性。然而，这些数据确立了抗坏血酸在肾上腺嗜铬细胞功能中的关键作用。
Ascorbic acid ( vitamin C) is a cofactor required in catecholamine synthesis for conversion of dopamine to norepinephrine by dopamine beta-hydroxylase. Mutant mice lacking the plasma membrane ascorbic acid transporter (SVCT2) have severely reduced tissue levels of ascorbic acid and die after birth. We therefore investigated whether these mice might have impaired synthesis of catecholamines. Levels of catecholamines in brain were unaffected by SVCT2 deficiency. In heart, the only evidence for impaired dopamine beta-hydroxylase activity was a twofold increase in tissue dopamine. An influence of the deficiency on tissue catecholamines was most prominent in the adrenals where norepinephrine was decreased by 50% and epinephrine, by 81%. On the ultrastructural level, adrenal chromaffin cells in SVCT2 null mice showed depletion of catecholamine storage vesicles, increased amounts of rough endoplasmic reticulum, signs of apoptosis, and increased glycogen storage. Decreased plasma levels of corticosterone indicated additional effects of the deficiency on adrenal cortical function. These data show that deranged catecholamine system function in SVCT2 null mice is largely restricted to the adrenal medulla and cannot account for the lethality in these animals. The data, however, establish a crucial role for ascorbic acid in adrenal chromaffin cell function.