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Willmes, D.M. ; Daniels, M. ; Kurzbach, A. ; Lieske, S.* ; Bechmann, N.* ; Schumann, T. ; Henke, C. ; El-Agroudy, N.N. ; da Costa Goncalves, A.C.* ; Peitzsch, M.* ; Hofmann, A.* ; Kanczkowski, W.* ; Kräker, K.* ; Müller, D.N.* ; Morawietz, H.* ; Deussen, A.* ; Wagner, M.* ; El-Armouche, A.* ; Helfand, S.L.* ; Bornstein, S.R.* ; de Cabo, R.* ; Bernier, M.* ; Eisenhofer, G.* ; Tank, J.* ; Jordan, J.* ; Birkenfeld, A.L.

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

JCI insight 6:e136083 (2021)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 2379-3708

e-ISSN 2379-3708

Journal JCI insight

Quellenangaben Volume: 6, Issue: 2, Article Number: e136083

Publisher Clarivate

Publishing Place Ann Arbor, Michigan

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Pancreatic Beta Cell Research (IPI)
Institute of Diabetes Research and Metabolic Diseases (IDM)

Grants Deutsche Forschungsgemeinschaft