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| Item Type: | Article |
|---|---|
| Title: | The longevity gene mIndy (I'm Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms. |
| Creators Name: | 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. and Birkenfeld, A.L. |
| 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. |
| Keywords: | Adrenal Glands, Blood Pressure, Caloric Restriction, Cardiovascular Models, Catecholamines, Cell Line, Chromaffin Cells, Dicarboxylic Acid Transporters, Gene Expression, Heart Rate, Inbred C57BL Mice, Knockout Mice, Longevity, Malates, Motor Activity, Pyridines, Sympathoadrenal System, Symporters, Animals, Mice |
| Source: | JCI Insight |
| ISSN: | 2379-3708 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 6 |
| Number: | 2 |
| Page Range: | 136083 |
| Date: | 25 January 2021 |
| Official Publication: | https://doi.org/10.1172/jci.insight.136083 |
| PubMed: | View item in PubMed |
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