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

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.

SUBMITTER: Willmes DM

PROVIDER: S-EPMC7934862 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Willmes Diana M DM Daniels Martin M Kurzbach Anica A Lieske Stefanie S Bechmann Nicole N Schumann Tina T Henke Christine C El-Agroudy Nermeen N NN Da Costa Goncalves Andrey C AC Peitzsch Mirko M Hofmann Anja A Kanczkowski Waldemar W Kräker Kristin K Müller Dominik N DN Morawietz Henning H Deussen Andreas A Wagner Michael M El-Armouche Ali A Helfand Stephen L SL Bornstein Stephan R SR de Cabo Rafael R Bernier Michel M Eisenhofer Graeme G Tank Jens J Jordan Jens J Birkenfeld Andreas L AL

JCI insight 20210125 2

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 catecho ...[more]

PMID: 33491666

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Project description:ObjectivesIn the United Kingdom, three people die every day awaiting an organ transplant. To address this, Scotland and England plan to follow Wales and introduce opt-out donor consent. However, emotional barriers, myths, and misconceptions may deter potential registrants. Our objectives were to estimate the number of people who plan to opt-out of the donor register and to test whether emotional barriers (e.g., medical mistrust) differentiated participants within this group. Finally, in an experimental manipulation, we tested whether intention to donate decreased by making emotional barriers more salient and increased following a widely used myth-busting intervention.DesignMixed between-within design.MethodsUK residents (n = 1,202) were asked whether they would choose opt-in, deemed consent, or opt-out/not sure if legislation changes to opt-out. Participants also completed measures of donor intentions at baseline, following a 12-item emotional barriers questionnaire and again, following a 9-item myth-busting intervention.ResultsFindings indicate that 66.1% of participants selected to opt-in to the donor register, 24.3% selected deemed consent, and 9.4% selected opt-out/not sure. Emotional barriers, notably fears surrounding bodily integrity, were significantly elevated in participants who selected opt-out/not sure. Increasing the salience of emotional barriers reduced donor intentions in the opt-out/not sure group. However, dispelling organ donation myths did not increase intention within this group.ConclusionsIf opt-out legislation is introduced in Scotland and England, approximately 10% of participants plan to opt-out or are not sure. Dispelling organ donation myths with facts may not be the best method of overcoming emotional barriers and increasing donor intentions for those planning to opt-out. Statement of contribution What is already known about this subject? In the United Kingdom, three people die every day waiting for an organ transplant. Although 90% of the UK population support organ donation, only 38% are registered donors. To address this, Scotland and England have recently proposed to introduce an opt-out system of donor consent. To date, limited research has investigated public attitudes and intentions regarding opt-out consent laws in Scotland and England. Emotional barriers (e.g., medical mistrust) are key factors that may deter potential registrants. However, no research has examined these barriers in relation to proposed opt-out consent laws. Myth-busting is widely used around the world as part of campaigns promoting organ donation. The NHS currently use a myth-busting feature on their webpage to dispel harmful myths about organ donation; however, there is limited evidence of the impact this has on intentions to become an organ donor. What does this study add? Approximately 10% of UK participants plan to opt-out or are unsure of their decision, if the law changes to opt-out. Emotional barriers, notably, bodily integrity fears, are significantly elevated in people who plan to opt-out. Increasing the salience of emotional barriers reduced donor intentions for people who plan to opt-out. A myth-busting intervention had no effect on donor intentions for people who plan to opt-out of the donor register.

Project description:BackgroundAlthough nitroglycerin has remained in clinical use since 1879, the mechanism by which it relaxes blood vessels to lower blood pressure remains incompletely understood. Nitroglycerin undergoes metabolism that generates several reaction products, including oxidants, and this bioactivation process is essential for vasodilation. Protein kinase G (PKG) mediates classic nitric oxide-dependent vasorelaxation, but the 1α isoform is also independently activated by oxidation that involves interprotein disulfide formation within this homodimeric protein complex. We hypothesized that nitroglycerin-induced vasodilation is mediated by disulfide activation of PKG1α.Methods and resultsTreating smooth muscle cells or isolated blood vessels with nitroglycerin caused PKG1α disulfide dimerization. PKG1α disulfide formation was increased in wild-type mouse aortas by in vivo nitroglycerin treatment, but this oxidation was lost as tolerance developed. To establish whether kinase oxidation underlies nitroglycerin-induced vasodilation in vivo, we used a Cys42Ser PKG1α knock-in mouse that cannot transduce oxidant signals because it does not contain the vital redox-sensing thiol. This redox-dead knock-in mouse was substantively deficient in hypotensive response to nitroglycerin compared with wild-type littermates as measured in vivo by radiotelemetry. Resistance blood vessels from knock-ins were markedly less sensitive to nitroglycerin-induced vasodilation (EC(50)=39.2 ± 10.7 μmol/L) than wild-types (EC(50)=12.1 ± 2.9 μmol/L). Furthermore, after ≈24 hours of treatment, wild-type controls stopped vasodilating to nitroglycerin, and the vascular sensitivity to nitroglycerin was decreased, whereas this tolerance phenomenon, which routinely hampers the management of hypertensive patients, was absent in knock-ins.ConclusionsPKG1α disulfide formation is a significant mediator of nitroglycerin-induced vasodilation, and tolerance to nitroglycerin is associated with loss of kinase oxidation.

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

Publications

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

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