Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog.
The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga mice. Loss of the physiological "brake" catestatin in Chga mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.
Mahapatra
Nitish R
NR
Department of Medicine, UCSD, San Diego, CA, USA.
O'Connor
Daniel T
DT
Vaingankar
Sucheta M
SM
Hikim
Amiya P Sinha
AP
Mahata
Manjula
M
Ray
Saugata
S
Staite
Eugenie
E
Wu
Hongjiang
H
Gu
Yusu
Y
Dalton
Nancy
N
Kennedy
Brian P
BP
Ziegler
Michael G
MG
Ross
John
J
Mahata
Sushil K
SK
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002837:Chromaffin Granules / Q000473:pathology / Q000502:physiology; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics* / Q000502:physiology*; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D004837:Epinephrine / Q000097:blood; D018390:Gene Targeting; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009478:Neuropeptide Y / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D012083:Renin / Q000097:blood
C506150:CHGA protein, human; D053379:Chromogranin A; D002864:Chromogranins; D009478:Neuropeptide Y; C506155:chromogranin A, mouse; D012083:Renin; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine