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. mINDY-knockout (KO) mice were monitored using radiotelemetry; autonomic cardiovascular control was assessed by pharmacological testing, spectral analysis, urine catecholamines and adrenal transcriptome analysis. In vivo echocardiography, vascular function and steroid hormones were assessed. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice compared to littermate controls. Urinary catecholamines were reduced 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. Adrenal size, histological structure and cardiac function were not affected. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. mIndy deletion recapitulates beneficial cardiovascular and metabolic responses to caloric restriction making it an attractive therapeutic target. Transcriptional changes in mINDY knock-out (KO) versus WT littermate adrenals were assayed (N=5 biological repeats per condition) using gene expression microarray analysis.