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

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.

[1]  S. Bornstein,et al.  Anti-Tumorigenic and Anti-Metastatic Activity of the Sponge-Derived Marine Drugs Aeroplysinin-1 and Isofistularin-3 against Pheochromocytoma In Vitro , 2018, Marine drugs.

[2]  Yulan Sheng,et al.  The crosstalk between autonomic nervous system and blood vessels. , 2018, International journal of physiology, pathophysiology and pharmacology.

[3]  J. Mariani,et al.  Comparable Attenuation of Sympathetic Nervous System Activity in Obese Subjects with Normal Glucose Tolerance, Impaired Glucose Tolerance, and Treatment Naïve Type 2 Diabetes following Equivalent Weight Loss , 2016, Front. Physiol..

[4]  G. Shulman,et al.  Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5) , 2015, Aging.

[5]  P. Loria,et al.  Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5) , 2015, Scientific Reports.

[6]  A. Birkenfeld,et al.  Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2 , 2015, Aging.

[7]  L. Gandía,et al.  A physiological view of the central and peripheral mechanisms that regulate the release of catecholamines at the adrenal medulla , 2007, Acta physiologica.

[8]  D. Goldstein,et al.  Clinical Catecholamine Neurochemistry: A Legacy of Julius Axelrod , 2006, Cellular and Molecular Neurobiology.

[9]  G. Grassi,et al.  Clinical benefits of a consistent reduction in blood pressure. , 1998, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[10]  J. Floras Inhibitory effect of atrial natriuretic factor on sympathetic ganglionic neurotransmission in humans. , 1995, The American journal of physiology.

[11]  L. Landsberg,et al.  Diet-induced changes in sympathoadrenal activity: implications for thermogenesis. , 1981, Life sciences.

[12]  H. Lehnert,et al.  Principles of catecholamine biosynthesis, metabolism and release. , 2004, Frontiers of hormone research.

[13]  C. White,et al.  Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats. , 2000, Hypertension.

[14]  S. Julius,et al.  Consequences of the increased autonomic nervous drive in hypertension, heart failure and diabetes. , 1998, Blood pressure. Supplement.