期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 115, 期 7, 页码 1942-1952出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI24354
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资金
- NHLBI NIH HHS [P01 HL58120, U01 HL69758, U01 HL069758, P01 HL058120] Funding Source: Medline
- NICHD NIH HHS [HD 39293, R01 HD039293] Funding Source: Medline
- NIDA NIH HHS [R29 DA011311, R29 DA11311] Funding Source: Medline
- NIDDK NIH HHS [R01 DK060702, DK 60702] Funding Source: Medline
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 Chya(-/-) 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.
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