TY - JOUR
T1 - The longevity gene mIndy (I’m Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms
AU - Willmes, Diana M.
AU - Daniels, Martin
AU - Kurzbach, Anica
AU - Lieske, Stefanie
AU - Bechmann, Nicole
AU - Schumann, Tina
AU - Henke, Christine
AU - El-Agroudy, Nermeen N.
AU - da Costa Goncalves, Andrey C.
AU - Peitzsch, Mirko
AU - Hofmann, Anja
AU - Kanczkowski, Waldemar
AU - Kräker, Kristin
AU - Müller, Dominik N.
AU - Morawietz, Henning
AU - Deussen, Andreas
AU - Wagner, Michael
AU - El-Armouche, Ali
AU - Helfand, Stephen L.
AU - Bornstein, Stephan R.
AU - de Cabo, Rafael
AU - Bernier, Michel
AU - Eisenhofer, Graeme
AU - Tank, Jens
AU - Jordan, Jens
AU - Birkenfeld, Andreas L.
N1 - Funding Information:
We thank Ilona Kamer, Julia Paditz, Doreen Ussath, Birgit Zatschler, Manja Neve, and Tina Fleischer for their excellent technical support in these studies. We acknowledge Elin Lehrmann and Yongqing Zhang at NIA for their expertise in microarray analysis. This research was supported in part by the Deutsche For-schungsgemeinschaft (DFG) within the CRC/Transregio 205/1, “The Adrenal: Central Relay in Health and Disease” to GE, as well as a grant from the Deutsche HypertonieLiga to ALB and a grant from the DFG to ALB (BI1292/ 4-2, 10-1;12-1 and IRTG 2251).
Funding Information:
We thank Ilona Kamer, Julia Paditz, Doreen Ussath, Birgit Zatschler, Manja Neve, and Tina Fleischer for their excellent technical support in these studies. We acknowledge Elin Lehrmann and Yongqing Zhang at NIA for their expertise in microarray analysis. This research was supported in part by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1, ?The Adrenal: Central Relay in Health and Disease? to GE, as well as a grant from the Deutsche HypertonieLiga to ALB and a grant from the DFG to ALB (BI1292/ 4-2, 10-1;12-1 and IRTG 2251).
Publisher Copyright:
Copyright: © 2021, Willmes et al.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/25
Y1 - 2021/1/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099945713&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.136083
DO - 10.1172/jci.insight.136083
M3 - Article
AN - SCOPUS:85099945713
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 2
M1 - e136083
ER -