Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension.
BACKGROUND
Hypertension is a complex trait with an ill-defined genetic predisposition, in which adrenergic mechanisms seem to be involved even at the early stages. Chromogranin A is a pro-hormone stored and released with catecholamines by exocytosis; its fragment catestatin, formed in vivo, inhibits further catecholamine release as an antagonist at the physiologic trigger for secretion, the neuronal nicotinic cholinergic receptor.


METHODS
We measured catestatin by radioimmunoassay in n = 277 subjects stratified by blood pressure (n = 61 hypertensive, n = 216 normotensive), and if normotensive by genetic risk of developing hypertension: family history positive (n = 176) versus negative (n = 40). Maximum likelihood analysis tested for bimodality. Involvement of catestatin in pathophysiology was probed by measurements of catecholamines and leptin, and the hemodynamic responses to environmental (cold) stress.


RESULTS
The normotensive offspring of patients with hypertension already had diminished catestatin (P = 0.024), and family history was a better predictor of catestatin than age, ethnicity or gender (P = 0.014). Greater catestatin variance among family history-positive individuals (P = 0.021) suggested heterogeneity in this group, and a bimodal distribution (P < 0.001) identified 4.3% of individuals in a lower mode of catestatin values, all with positive family histories (P = 0.05). Catestatin correlated inversely with body mass index (r = -0.215, r(2) = 0.046, n = 276, P < 0.001) and plasma leptin (r = -0.203, r(2) = 0.041, n = 212, P = 0.003), while body mass index and leptin correlated directly (r = 0.59, r(2) = 0.350, n = 212, P < 0.001). Family history-positive individuals had greater epinephrine excretion (P = 0.037) in addition to diminished catestatin, suggesting an inhibitory effect of catestatin on chromaffin cells in vivo. Low plasma catestatin predicted enhanced pressor response to a sympathoadrenal stressor (cold stress; r = -0.184, r(2) = 0.034, n = 211, P = 0.007), suggesting an adrenergic mechanism whereby diminished catestatin might predispose to later development of hypertension. In white subjects, diminished catestatin also predicted greater systemic vascular resistance responses to cold stress (r = -0.307, r(2) = 0.094, n = 75, P = 0.007), a relationship not found in Blacks (r = 0.122, r(2) = 0.015, n = 94, P = 0.243).


CONCLUSIONS
We conclude that catestatin is diminished early in the course of development of hypertension, even in the normotensive offspring of patients with the disease. Low catestatin predicts augmented adrenergic pressor responses, suggesting a mechanism whereby diminished catestatin might increase the risk for later development of hypertension.
Department of Medicine and Center for Molecular Genetics, University of California and V.A. San Diego Healthcare System, San Diego, California, USA. doconnor@ucsd.edu
Daniel T
DT
O'Connor
Mala T
MT
Kailasam
Brian P
BP
Kennedy
Michael G
MG
Ziegler
Noboru
N
Yanaihara
Robert J
RJ
Parmer
D000328:Adult; D002140:California; D002395:Catecholamines / Q000235:genetics* / Q000378:metabolism*; D053379:Chromogranin A; D002864:Chromogranins / Q000097:blood* / Q000235:genetics*; D003080:Cold Temperature; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006439:Hemodynamics / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000208:ethnology / Q000235:genetics*; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000097:blood / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics*; D011237:Predictive Value of Tests; D013223:Statistics as Topic; D013312:Stress, Physiological; D013997:Time Factors
D002395:Catecholamines; D053379:Chromogranin A; D002864:Chromogranins; D005819:Genetic Markers; D020738:Leptin; D010446:Peptide Fragments; C109084:chromogranin A (344-364)