Catecholamine storage vesicle protein expression in genetic hypertension.
Chromogranin A expression is heritable in humans, and both plasma chromogranin A concentration and its releasable adrenal and sympathetic neuronal pools are augmented in established essential (hereditary) hypertension. To evaluate chromogranin A further as a simpler or "intermediate phenotype" in the complex trait of hypertension, we studied chromogranin A expression in the spontaneously hypertensive rat (SHR), a rodent model of essential hypertension. Both plasma (p < 0.0001) and adrenal medullary (p = 0.003 to p < 0.0001) chromogranin A were elevated in the SHR, even at the earliest stages (3-4 weeks of age). In the adult adrenal gland, both chromogranin A (p=0.005) and norepinephrine (p=0.011) were increased in the SHR, while dopamine beta-hydroxylase activity was diminished (p < 0.0001). Chromogranin A mRNA expression was also elevated in the SHR adrenal medulla (p = 0.017). Differences in chromogranin A processing were not noted between SHR and Wistar Kyoto control (WKY) rats. In an SHR x WKY genetic intercross, control of the adrenal chromogranin A phenotype by a single major locus was suggested by comparison of phenotypic variance of the F2 vs F1 generations, and by bimodal frequency histogram (3:1 ratio), confirmed by maximum likelihood analysis (chi2 = 74.6, p < 0.000001) in the F2 generation. However, microsatellite alleles at a surrogate locus (Ighe) 12.7 cM from chromogranin A (Chga), on rat chromosome 6, failed to co-segregate with blood pressure in an F2 generation (F = 0.06, p = 0.94). In another rodent model of hereditary hypertension, the genetically hypertensive mouse (BPH/2), adrenal chromogranin A (p=0.018) and norepinephrine (p = 0.004) were actually diminished. We conclude that over-expression of chromogranin A is a variable feature of mammalian genetic hypertension. In one rodent model (the SHR), over-expression of chromogranin A is largely controlled by a single genetic locus, but the chromogranin A locus itself is not directly linked to determination of the blood pressure elevation of the SHR.
O'Connor
D T
DT
Department of Medicine, Center for Molecular Genetics, University of California, V.A. San Diego Healthcare System, USA. doconnor@ucsd.edu
Takiyyuddin
M A
MA
Printz
M P
MP
Dinh
T Q
TQ
Barbosa
J A
JA
Rozansky
D J
DJ
Mahata
S K
SK
Wu
H
H
Kennedy
B P
BP
Ziegler
M G
MG
Wright
F A
FA
Schlager
G
G
Parmer
R J
RJ
D000313:Adrenal Medulla / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002395:Catecholamines / Q000378:metabolism; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics* / Q000378:metabolism; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D002395:Catecholamines; D053379:Chromogranin A; D002864:Chromogranins; D017931:DNA Primers; D012333:RNA, Messenger