The longevity gene mIndy (I’m Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms

Diana M. Willmes, Martin Daniels, Anica Kurzbach, Stefanie Lieske, Nicole Bechmann, Tina Schumann, Christine Henke, Nermeen N. El-Agroudy, Andrey C. da Costa Goncalves, Mirko Peitzsch, Anja Hofmann, Waldemar Kanczkowski, Kristin Kräker, Dominik N. Müller, Henning Morawietz, Andreas Deussen, Michael Wagner, Ali El-Armouche, Stephen L. Helfand, Stephan R. BornsteinRafael de Cabo, Michel Bernier, Graeme Eisenhofer, Jens Tank, Jens Jordan, Andreas L. Birkenfeld*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere136083
JournalJCI Insight
Volume6
Issue number2
DOIs
Publication statusPublished - 25 Jan 2021

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