Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )

Abstract

Background-Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. Methods and Results-Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by Ϸ47%) and downward deflections (by Ϸ44%), increased cardiac parasympathetic index (by Ϸ2.4-fold), and decreased cardiac sympathetic index (by Ϸ26%). Renal norepinephrine excretion was diminished by Ϸ26% and epinephrine excretion by Ϸ34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to Ϸ70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by Ϸ5 to 6 mm Hg, and the polymorphism accounted for Ϸ1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. Conclusions-The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

Urinary norepinephrine and epinephrine excretion rates are heritable, but not associated with office and ambulatory blood pressure

“…This is indeed supported by our present results, showing heritabilities on par or exceeding those previously reported for blood 5,12 and urinary 12 catecholamines measured during the daytime. Urinary catecholamine levels in the studies by Zhang et al 14 and Rao et al 6,40,41 were normalized for creatinine excretion in the same sample, but it is not clear whether 24 h, overnight or spot urine was used, which complicates meaningful comparisons with our study. Several studies have reported associations between genetic polymorphisms and catecholamine secretion.…”

“…Renal NE excretion was diminished by around 26% and E excretion by around 34% in Gly/Ser heterozygotes. 40 Another study performed in a similar sample suggested that common tyrosine hydroxylase (TH) promoter polymorphisms with variants at C-824T and A-581G showed significant associations with urinary catecholamine excretion. 41 C-824T also exerted significant pleiotropic effects on the coupling between blood pressure response to cold stress and urinary NE.…”

Hereditary Determinants of Human Hypertension

“…Consistent with the individual SNP analyses, an ADRA2A haplotype influenced BP only in women, whereas 2 AGT haplotypes affected BP only in men. 22 Sex-dependent genetic effects in hypertension were also noted for genetic variants at TH, 8 chromogranin A (CHGA), 26 GCH1, 10 and the estrogen receptor genes (ER␣ and ER␤). 27 Such findings raise the possibility that previous genetic studies failing to find associations with hypertension might have overlooked the importance of sex-by-gene interaction effects.…”

Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

“…catestatin acts to stabilize baseline conditions in several in vivo and in vitro models (2,5,15,30,34,48). As such, the role of catestatin may not be apparent until an appropriate stimulus is applied.…”