Section of Metabolic and Vascular Medicine, Medical Clinic III, University Hospital and Medical Faculty Carl Gustav Carus and.
Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, Technical University Dresden, Dresden, Germany.
JCI Insight. 2021 Jan 25;6(2):136083. doi: 10.1172/jci.insight.136083.
Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.
质膜柠檬酸转运蛋白 INDY（缩写为 I'm Not Dead, Yet）表达减少可延长低等生物的寿命。在啮齿动物中删除哺乳动物 Indy（mIndy）基因可通过类似于热量限制的机制改善代谢，已知热量限制通过交感肾上腺抑制降低血压（BP）。我们假设 mIndy 缺失可减弱 BP 的交感肾上腺支持。mINDY-KO 小鼠的动脉血压和心率（HR）持续降低。同时，尿儿茶酚胺含量降低，并且 mIndy 缺失引起的 BP 和 HR 降低在自主神经节阻断后减弱。使用无偏微阵列分析发现，mINDY-KO 肾上腺中的儿茶酚胺生物合成途径减少。柠檬酸是 mINDY 的主要底物，可增加嗜铬细胞瘤细胞中的儿茶酚胺含量，而柠檬酸摄取的药理学抑制则削弱了这种作用。我们的数据表明，mIndy 的缺失通过减弱儿茶酚胺生物合成来降低 BP 和 HR 的交感肾上腺支持。mIndy 的缺失再现了热量限制对心血管和代谢的有益反应，使其成为一个有吸引力的治疗靶点。
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