Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog
Nitish R. Mahapatra, … , John Ross Jr., Sushil K. Mahata
Nitish R. Mahapatra, … , John Ross Jr., Sushil K. Mahata
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1942-1952. https://doi.org/10.1172/JCI24354.
View: Text | PDF
Research Article Cardiology

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog

Abstract

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.

Authors

Nitish R. Mahapatra, Daniel T. O’Connor, Sucheta M. Vaingankar, Amiya P. Sinha Hikim, Manjula Mahata, Saugata Ray, Eugenie Staite, Hongjiang Wu, Yusu Gu, Nancy Dalton, Brian P. Kennedy, Michael G. Ziegler, John Ross Jr., Sushil K. Mahata

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
Autonomic/cardiovascular physiology. (A) SBP measured by the tail-cuff m...
Autonomic/cardiovascular physiology. (A) SBP measured by the tail-cuff method in Chga+/+ (n = 8), Chga+/– (n = 14), and Chga–/– (n = 8) conscious male mice during restraint at 5–6 months of age. (B) Continuous telemetric data from unrestrained mice on SBP and DBP over a 24-hour period in Chga+/+ (n = 5) and Chga–/– (n = 7) mice. (C) Telemetric data on DBP over a 24-hour period in Chga+/+ (n = 5) and Chga–/– (n = 7) mice. (D) Rescue from elevated SBP by the CHGA catecholamine release–inhibitory fragment catestatin: exaggerated SBP fall in Chga–/– mice. SBP was monitored by telemetry before and after administration of catestatin (20 nmol/25 g body weight, i.p.) at time 0 in Chga–/– (n = 4) and Chga+/+ (n = 4) mice. Results were analyzed by 2-way, repeated-measures ANOVA, evaluating the effects of time (F = 359.9; P < 0.001), mouse strain (Chga+/+ vs. Chga–/–; F = 14.8; P = 0.009), or strain/peptide interaction (F = 79.4; P < 0.001). (E) Transthoracic echocardiography in Chga+/+ (n = 8) and Chga–/– (n = 8) mice. LVIDd, LV dimension at end diastole; LVIDs, LV dimension at end systole; IVSd, interventricular septal thickness at end diastole; IVSs, interventricular septal thickness at end systole; LVPWd, LV posterior wall thickness at end diastole; LVPWs, LV posterior wall thickness at end systole.