Effects of chromogranin A deficiency and excess in vivo: biphasic blood pressure and catecholamine responses.
OBJECTIVE
The phenotype of the chromogranin A (Chga) null (knockout) mouse is hypertensive. However, hypertensive humans and spontaneously hypertensive rats display elevated CHGA expression. This study addresses the paradox that both ablation and elevation of CHGA result in hypertension.


METHODS
Mice with varying copy number of the CHGA gene were generated. In these mice CHGA, catecholamine and blood pressure (BP) were measured. Also a cohort of healthy human individuals was stratified into tertiles based on plasma CHGA expression and phenotyped for characteristics including their BP response to environmental (cold) stress.


RESULTS
The mice displayed a direct CHGA gene dose-dependent (0-4 copies/genome) activation of CHGA expression in both plasma and adrenal gland, yet the BP dependence of CHGA gene dose was U-shaped, maximal at 0 and four copies of the gene, whereas minimal at two copies (i.e., the wild-type gene dosage). Plasma catecholamine showed a parallel U-shaped dose/response in mice, whereas adrenal epinephrine exhibited a reciprocal (inverted) U-shaped response, suggesting dysregulated neurotransmission at both extremes of CHGA expression. The human individuals also showed a nonlinear relationship between CHGA expression and pressor responses to environmental (cold) stress, that were maximal in the highest and lowest tertiles, though basal BPs did not differ among the groups. The human CHGA tertiles also differed in epinephrine secretion as well as degree of CHGA processing to catestatin (catecholamine release-inhibitory peptide derived from CHGA processing).


CONCLUSIONS
Thus, across mammalian species, an optimal amount of CHGA may be required to establish appropriate catecholamine storage and release, and hence BP homeostasis.
Department of Medicine, University of California at San Diego, and Veterans Affairs San Diego Healthcare System, La Jolla, California 92093-0838, USA. svaingankar@ucsd.edu
Sucheta M
SM
Vaingankar
Ying
Y
Li
Nilima
N
Biswas
Jiaur
J
Gayen
Sonia
S
Choksi
Fangwen
F
Rao
Michael G
MG
Ziegler
Sushil K
SK
Mahata
Daniel T
DT
O'Connor
D000311:Adrenal Glands / Q000378:metabolism / Q000503:physiopathology; D000328:Adult; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D002395:Catecholamines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053379:Chromogranin A / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015331:Cohort Studies; D004837:Epinephrine / Q000097:blood; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D051381:Rats; D011918:Rats, Inbred SHR; D013312:Stress, Physiological
D002395:Catecholamines; D053379:Chromogranin A; D004837:Epinephrine