| Literature DB >> 33491666 |
Diana M Willmes1,2,3, Martin Daniels1,2,3,4,5, Anica Kurzbach1,2,3,4,5,6, Stefanie Lieske1, Nicole Bechmann7, Tina Schumann1,2,3, Christine Henke1,2,3, Nermeen N El-Agroudy1,2,3,6, Andrey C Da Costa Goncalves8, Mirko Peitzsch7, Anja Hofmann9, Waldemar Kanczkowski1,6, Kristin Kräker10, Dominik N Müller10, Henning Morawietz9, Andreas Deussen11, Michael Wagner12, Ali El-Armouche12, Stephen L Helfand13, Stephan R Bornstein1,6, Rafael de Cabo14, Michel Bernier14, Graeme Eisenhofer1,7, Jens Tank15, Jens Jordan15,16, Andreas L Birkenfeld1,2,3,4,5,6.
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.Entities:
Keywords: Cardiovascular disease; Metabolism; Vascular Biology
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Year: 2021 PMID： 33491666 PMCID： PMC7934862 DOI： 10.1172/jci.insight.136083
Source DB: PubMed Journal: JCI Insight ISSN： 2379-3708