Naturally Occurring Genetic Variants in Human Chromogranin A (CHGA) Associated with Hypertension as well as Hypertensive Renal Disease

Article (PDF Available)inCellular and Molecular Neurobiology 30(8):1395-400 · November 2010with38 Reads
DOI: 10.1007/s10571-010-9600-2 · Source: PubMed
Abstract
Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive renal disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed both common and unusual variants in both the open reading frame and such regulatory regions as the proximal promoter and 30-UTR. In chromaffin cell-transfected CHGA 30-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 30-UTR displayed statistical associations with hypertension. Genetic variation in the proximal CHGA promoter predicted glomerular filtration rate in healthy twins. However, for hypertensive renal damage, both end-stage renal disease and rate of progression of earlier disease were best predicted by variants in the 30-UTR. Finally, mechanistic studies were undertaken initiated by the clue that CHGA promoter variation predicted circulating endothelin-1. In cultured endothelial cells, CHGA triggered co-release of not only the vasoconstrictor and pro-fibrotic endothelin-1, but also the pro-coagulant von Willebrand Factor and the pro-angiogenic angiopoietin-2. These findings, coupled with stimulation of endothelin-1 release from glomerular capillary endothelial cells by CHGA, suggest a plausible mechanism whereby genetic variation at the CHGA locus eventuates in alterations in human renal function. These results document the consequences of genetic variation at the CHGA locus for cardiorenal disease and suggest mechanisms whereby such variation achieves functional effects.
REVIEW PAPER
Naturally Occurring Genetic Variants in Human Chromogranin
A (CHGA) Associated with Hypertension as well as Hypertensive
Renal Disease
Yuqing Chen
Fangwen Rao
Gen Wen
Jiaur R. Gayen
Kuixing Zhang
Sucheta M. Vaingankar
Nilima Biswas
Manjula Mahata
Ryan S. Friese
Maple M. Fung
Rany M. Salem
Caroline Nievergelt
Vibha Bhatnagar
Vivian Y. Hook
Michael G. Ziegler
Sushil K. Mahata
Bruce A. Hamilton
Daniel T. O’Connor
Received: 11 May 2010 / Accepted: 7 September 2010 / Published online: 9 November 2010
Ó The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract Chromogranin A (CHGA) plays a fundamental
role in the biogenesis of catecholamine secretory granules.
Changes in storage and release of CHGA in clinical and
experimental hypertension prompted us to study whether
genetic variation at the CHGA locus might contribute to
alterations in autonomic function, and hence hypertension
and its target organ consequences such as hypertensive renal
disease (nephrosclerosis). Systematic polymorphism dis-
covery across the human CHGA locus revealed both com-
mon and unusual variants in both the open reading frame
and such regulatory regions as the proximal promoter and
3
0
-UTR. In chromaffin cell-transfected CHGA 3
0
-UTR and
promoter/luciferase reporter plasmids, the functional con-
sequences of the regulatory/non-coding allelic variants were
documented. Variants in both the proximal promoter and the
3
0
-UTR displayed statistical associations with hypertension.
Genetic variation in the proximal CHGA promoter predicted
glomerular filtration rate in healthy twins. However, for
hypertensive renal damage, both end-stage renal disease and
rate of progression of earlier disease were best predicted by
variants in the 3
0
-UTR. Finally, mechanistic studies were
undertaken initiated by the clue that CHGA promoter vari-
ation predicted circulating endothelin-1. In cultured endo-
thelial cells, CHGA triggered co-release of not only the
vasoconstrictor and pro-fibrotic endothelin-1, but also the
pro-coagulant von Willebrand Factor and the pro-angio-
genic angiopoietin-2. These findings, coupled with stimu-
lation of endothelin-1 release from glomerular capillary
endothelial cells by CHGA, suggest a plausible mechanism
whereby genetic variation at the CHGA locus eventuates in
alterations in human renal function. These results document
the consequences of genetic variation at the CHGA locus for
cardiorenal disease and suggest mechanisms whereby such
variation achieves functional effects.
Keywords CHGA Hypertension Hypertensive
nephrosclerosis
Abbreviations
3
0
-UTR 3
0
-Untranslated region (of mRNA)
5-HT Serotonin (5-hydroxy-tryptamine)
BP Blood pressure
A commentary to this article can be found at doi:
10.1007/s10571-010-9607-8.
Y. Chen
Renal Division, Peking University First Hospital,
Beijing 100034, China
F. Rao G. Wen J. R. Gayen K. Zhang
S. M. Vaingankar N. Biswas M. Mahata
R. S. Friese M. M. Fung R. M. Salem C. Nievergelt
V. Bhatnagar M. G. Ziegler S. K. Mahata
B. A. Hamilton D. T. O’Connor (&)
Department of Medicine (0838), UCSD School of Medicine and
VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA
e-mail: doconnor@ucsd.edu
URL: http://hypertension.ucsd.edu/
V. Y. Hook D. T. O’Connor
Department of Pharmacology, University of California
at San Diego, La Jolla, CA, USA
B. A. Hamilton D. T. O’Connor
Institute for Genomic Medicine, University of California
at San Diego, La Jolla, CA, USA
M. M. Fung S. K. Mahata D. T. O’Connor
VA San Diego Healthcare System, La Jolla, CA, USA
123
Cell Mol Neurobiol (2010) 30:1395–1400
DOI 10.1007/s10571-010-9600-2
CHGA, Chga Chromogranin A (uppercase: human,
lowercase: rodent)
CHGB, Chgb Chromogranin B (uppercase: human,
lowercase: rodent)
DBP Diastolic blood pressure
EDN1 Endothelin-1
ESRD End stage renal disease
GFR Glomerular filtration rate
siRNA Small interfering RNA
SBP Systolic blood pressure
TH Tyrosine hydroxylase
vWF von Willebrand factor
Introduction
Chromogranin A (CHGA: human, Chga: rodent) is the
major protein co-stored and co-released with catechola-
mines from secretory vesicles in adrenal medulla and
postganglionic sympathetic axons (Takiyyuddin et al.
1990b). CHGA is required for formation of catecholamine
secretory vesicles in chromaffin cells (Mahapatra et al.
2005) and its expression may be sufficient even to induce a
regulated secretory system in non-secretory cells (Kim et al.
2001). CHGA is also a pro-hormone that gives rise to bio-
logically active peptides such as the dysglycemic peptide
pancreastatin (Cadman et al. 2002; Tatemoto et al. 1986),
the antimicrobial peptide chromacin (Strub et al. 1996), the
vasodilator vasostatin, and catestatin that acts to inhibit
catecholamine release (Mahata et al. 1999, 1997). Proteo-
lytic enzymes specifically catalyzing CHGA cleavage to
active peptides have been identified including the pro-hor-
mone convertases (Eskeland et al. 1996), plasmin (Jiang
et al. 2001; Parmer et al. 2000; Biswas et al. 2008), and
cathepsin L (Biswas et al. 2009).
Over the past *20 years, phenotypic links between
CHGA and hereditary (essential, idiopathic, and genetic)
human (Hsiao et al. 1991; O’Connor 1985; Takiyyuddin
et al. 1990a) and rodent (O’Connor et al. 1999; Fries et al.
2004) hypertension have been repeatedly observed. Plasma
CHGA concentration correlates with catecholamine release
rates (Dimsdale et al. 1992), and increases in blood pressure
caused by the action of catecholamines may be coupled to
the formation of dense-core secretory granules, whose bio-
genesis is regulated in vivo by CHGA (Mahapatra et al.
2005). Increased serum CHGA has been detected not only in
patients with essential hypertension (O’Connor 1985) but
also hypertensive consequences such as cardiac or renal
(Hsiao et al. 1990) failure. Intriguingly, targeted ablation of
the Chga locus in the mouse also results in elevated BP
(Mahapatra et al. 2005) and global autonomic dysfunction,
both sympathetic and parasympathetic (Gayen et al. 2009);
recently, using both knockout and replacement strategies,
we established that Chga gene copy number exhibits a
biphasic (or ‘U-shaped’’) effect on both BP and catechol-
amine release (Vaingankar et al. 2010a, b); we observed
parallel findings on CHGA secretion and autonomic stress
responses in humans (Vaingankar et al. 2010a, b), suggest-
ing that an optimal amount of CHGA may be required to
establish appropriate catecholamine storage and release, and
hence BP homeostasis.
We systematically identified genetic variation across the
human CHGA locus by resequencing the gene in several
human populations (Wen et al. 2004). We then explored
whether common genetic variation at the CHGA locus is
associated with hypertension or hypertensive complications
such as nephrosclerosis beginning with large population-
based samples. We then established an influence on an
earlier pathogenic phenotype (environmental stress-evoked
change in BP), and finally documented the effects on gene
expression in transfected reporter systems in chromaffin
cells.
Chromogranin A Genetic Variants and Hypertension
A common haplotype of the CHGA proximal promoter
region, CGATA (at T-1014C, T-988G, G-462A, C-415T,
and A-89C), blunted the BP response to cold stress, and the
response exhibited molecular heterosis (most extreme phe-
notype in heterozygotes) between the two most common
promoter haplotypes (CGATA/TTGTC) (Chen et al.
2008a). Homozygosity for the minor alleles at T-1014C
(C/C), T-988G (G/G), and G-462A (A/A) predicted lower
stress BP increments with peak prediction for G-462A
(rs9658634) heterozygotes (*6–7 mmHg). G-462A also
predicted resting BP in the population, accounting for
*3/2 mmHg SBP/DBP, once again with the appearance of
molecular heterosis (i.e., highest BP in G/A heterozygotes).
In transfected CHGA promoter/luciferase reporters,
CGATA had diminished expression compared to TTGTC,
under both basal conditions and after secretory activation by
pre-ganglionic stimuli (nicotinic cholinergic, VIP). Variant
G-462A altered a COUP-TF transcriptional control motif
and the two alleles in transfected promoters differed in basal
activity (G [ A), as well as the response to COUP-II-TF
(A [ G) and retinoic acid (G [ A). Findings of molecular
heterosis were also demonstrated for the transfected CHGA
promoter in cella, wherein the diploid combination of the
two alleles at G-462A (G/A heterozygosity) gave rise to
greater luciferase expression than either allele in isolation
(Chen et al. 2008a).
A common (*27% allele frequency) genetic variant in
the CHGA 3
0
-UTR (C ? 87T; rs7610) was strongly asso-
ciated with human essential hypertension, accounting for up
1396 Cell Mol Neurobiol (2010) 30:1395–1400
123
to *12/9 mmHg of BP in men, or *1.9/1.2% of population
SBP/DBP variance, especially in males (Chen et al. 2008b).
The 3
0
-UTR variant also predicts environmental stress-
induced increments in blood pressure: the same allele
(?87T) that diminished basal BP in the population also
decreased the SBP response to stress by *12 mmHg
(P = 0.017), and the response was smaller in women (by
*6 mmHg, P = 0.009), suggesting a mechanism for early
effects of the gene on a pathogenic series of events even-
tuating in sustained blood pressure elevation. The 3
0
-UTR
variant is in a region of sequence conservation across
species, and acts to change CHGA gene expression in chro-
maffin cells. In a chromaffin cell-transfected CHGA 3
0
-UTR/
luciferase reporter plasmid, the ?87T allele associated with
lower BP also decreased reporter expression by *30%
(P = 0.009). In cultured chromaffin cells, reducing endog-
enous Chga expression by siRNA caused *2/3 depletion of
catecholamine storage vesicles (P \ 0.0001). At multiple
levels (CHGA expression, heritable circulatory response to
environmental stress, and finally basal BP in the population),
sex seemed to play an important role in mediating the effect
of genetic variation on phenotype (Chen et al. 2008b).
Chromogranin A Genetic Variants: Renal Function
and Hypertensive Nephrosclerosis
In African-Americans with a clinical diagnosis of hyper-
tensive renal disease (or nephrosclerosis) (Salem et al.
2008), genetic variation at CHGA predicts risk for devel-
oping the trait, and the peak effect lies in haplotypes
spanning the 3
0
-end of the gene.
In a large twin pair sample with normal renal function,
glomerular filtration rate (GFR) was highly heritable (at
h
2
= 78 ± 3%, P \ 10
-25
), and CHGA common promoter
haplotypes (G-1106A, rs9658628; A-1018T, rs9658629;
T-1014C, rs9658630; T-988G, rs9658631; G-462A,
rs9658634; T-415C, rs9658635; C-89A, rs7159323;
C-57T, rs9658638) predicted GFR: haplotype-2 (GATT
GTCC) copy number was associated with higher GFR,
while haplotype-3 (GACGATAC) predicted lower GFR
(Chen et al. 2009).
In subjects from the NIDDK AASK (African-American
Study of Kidney Disease and Hypertension) trial, the
chronic decline rate of GFR was influenced by genetic
variation at CHGA, with the most prominent effect
(P = 0.006) from haplotype-1 in the 3
0
-haplotype block,
spanning 3
0
-UTR C ? 87T/rs7610 (Chen et al. 2009). The
effect was also seen for diploid haplotype pairs in that
block (P = 0.007).
We first noted association of CHGA genetic variation
with circulating endothelin-1 (EDN1) (Lillie et al. 2007),
and then found that CHGA genetic variation or secretion
predicted not only EDN1 but also renal traits in a large
series of twin and sibling pairs (Chen et al. 2009). Plasma
CHGA positively correlated with EDN1 and negatively
correlated with GFR. Thus we explored the possible
mechanisms of CHGA effects on GFR as well as pro-
gression of kidney disease in culture cells. CHGA released
EDN1 from HUVEC (human umbilical vein endothelial
cells), dependent upon extracellular Ca
2?
influx through
voltage-operated Ca
2?
channels, and inhibited by the 5-HT
(serotonin) antagonist cyproheptadine. The response was
also triggered by the CHGA synthetic amino terminus
(CHGA1-40). CHGA triggered endothelial co-release of
not only EDN1, but also von Willebrand Factor (vWF), and
angiopoietin-2, consistent with a global Weibel Palade
Body (i.e., endothelial secretory granule) exocytosis
response to CHGA. In renal glomerular cells, CHGA
caused secretion of EDN1 from glomerular endothelial
cells, and induced secretion of TGF-beta-1 from mesangial
cells co-cultured with glomerular endothelial cells, along
with TGF-beta-1 signal transduction (Chen et al. 2009).
In this series of studies of CHGA genetic variation on
disease, especially hypertension and hypertensive nephro-
sclerosis, we took advantage of multiple resources and
approaches, including intermediate phenotypes (biochem-
ical and/or physiological traits proceeding disease pheno-
types), different populations with replication, as well as
functional experiments in cella, to identify the pathways
whereby CHGA influences disease risk. Many of these
observations are consistent with the ‘common disease/
common allele’ hypothesis for frequent traits in the pop-
ulation, and suggest new molecular strategies for probing
the pathophysiology, risk, and rational treatment of
hypertension and hypertensive nephrosclerosis. Other
observations, such as those on the unusual (minor allele
frequency *6%) CHGA coding variant Gly364Ser, in the
catecholamine release-inhibitory ‘catestatin’’ region of the
protein, indicate a role for rare variants in prediction of
cardiovascular risk (Rao et al. 2007).
‘Intermediate’ Phenotypes
In the setting of late penetrance of the ultimate disease trait
(such as hypertension), as well as likely genetic heteroge-
neity, the ‘intermediate phenotype (Lillie and O’Connor
2006; Shih and O’Connor 2008) strategy may be a useful
approach in the search for disease predisposition loci.
Autonomic traits with heritable determination may be of
particular value in investigation of the genetic underpin-
nings of hypertension. In accordance with this pathway
concept, we pursued intermediate traits in these studies.
Secretion of CHGA, estimated by its plasma concentration,
as well as the hemodynamic response to environmental
Cell Mol Neurobiol (2010) 30:1395–1400 1397
123
stressors (such as cold), may be predictors of the devel-
opment of later cardiovascular events, such as hypertension
(Markovitz et al. 1998; Menkes et al. 1989; Schneider et al.
2003; Snieder et al. 2002; Treiber et al. 2003). Such
responses, occurring even prior to the onset of disease,
would be useful biochemical or physiological ‘intermedi-
ate’ phenotypes in probing the genetic determinants of
hypertension (Lillie and O’Connor 2006; O’Connor et al.
2000, 2002). When we analyzed the cold stress response in
our twin subjects, we found that that both change in BP and
final (post-stress) BP are heritable, and thus may constitute
valuable intermediate phenotypic anchor points for hyper-
tension (Chen et al. 2008a, b).
Molecular Heterosis
The CHGA common promoter haplotype homozygosity
(CGATA/CGATA) and individual SNP G-462A effects
were more extreme for heterozygotes, suggesting ‘molec-
ular heterosis’’. The phenomenon of molecular heterosis has
been defined as occurring when polymorphism at a single
genetic locus displays a significantly greater or lesser effect
on a quantitative trait than homozygosity at the same locus.
While the phenomenon may initially seem counter-intuitive,
it may be explained by one of several underlying mecha-
nisms, including a U-shaped dose–response relationship for
gene-on-trait, greater ‘fitness’ in heterozygotes, or hidden
stratification in one homozygote class. One such stratifica-
tion might be the effect of allelic variation at other (non-
CHGA) trans-QTLs on cold stress and basal BPs, such as the
associations we have reported for polymorphisms at tyro-
sine hydroxylase (TH) (Zhang et al. 2010a, b; Rao et al.
2007) or Rho kinase (ROCK2) (Seasholtz et al. 2006).
Sex: Role in Hypertension and Intermediate Phenotypes
In the wake of the sex-dependent effect of CHGA genetic
variation on BP, we question potential interactions of gene
and sex, and for CHGA we found that sex played a role at
each of several steps: biochemical, physiological, and
disease levels. Why adrenergic genetic variations yield
such different consequences in men and women? Acute
vascular responses to adrenergic stimuli are sex-dependent,
and the long-term consequences of repeated stressors on
resting blood pressure or the late appearance hypertension
differ by sex (Markovitz et al. 1998).
More recently, we established that common promoter
variation at two adrenergic loci, CHGB and TH (Zhang
et al. 2010a, b), disrupted DNA sequence matches for the
transcription factor SRY (Sex-determining Region Y), a
Y-chromosome-encoded HMG (high mobility group)-box
factor that may be instrumental in generating the male
phenotype, but which also has effects on gene expression in
the adult organism.
Chromogranin A and the Kidney: Potential Clinical
Implications
Since CHGA is important in storage and release of cate-
cholamines (Mahapatra et al. 2005; Vaingankar et al. 2010a,
b), and is associated with hypertension (Chen et al. 2009,
2008a), it was reasonable to explore whether CHGA might
have an effect on hypertensive nephrosclerosis, via cate-
cholamines or hypertension. In our initial study of pre-
dominantly healthy twin pairs (Lillie et al. 2007
), we found
that CHGA common genetic variation, especially in the
promoter region, predicted circulating EDN1 concentration.
We then found that CHGA polymorphism predicted the
occurrence of hypertensive renal disease in African-
Americans with the peak risk conferred by variation in the
3
0
-region of the gene (Salem et al. 2008).
We finally proceeded to more mechanistic studies (Chen
et al. 2009), attempting to understand the links between
CHGA genetic variation, EDN1, and renal function. Here
CHGA displayed effects on GFR in healthy individuals, as
well as GFR decline rate in subjects with progressive of
renal disease, and the effects seemed independent of blood
pressure. EDN1 suggested a candidate pathway for explo-
ration: we then identified CHGA-induced release of other
endothelial mediators that could influence renal function,
including the vasoconstrictor and pro-fibrotic EDN1, but
also the pro-coagulant vWF and the pro-angiogenic angio-
poietin-2. Co-release of all the three by CHGA from endo-
thelial cells was consistent with a mechanism whereby
CHGA triggered exocytosis of the endothelial cell secretory
granule: the Weibel Palade Body.
Why did a promoter block of CHGA best predict GFR in
healthy individuals, while a 3
0
block best predicted GFR
decline in subjects with renal dysfunction (Chen et al.
2009)? Transfected luciferase reporter studies of genetic
variants in these CHGA domains have now established that
variants in both the proximal promoter (Chen et al. 2008a)
and the 3
0
-UTR (Chen et al. 2008b) are functional, and thus
capable of influencing disease traits. In our previous case/
control studies of hypertensive renal disease, 3
0
-UTR vari-
ation was associated with ESRD (Salem et al. 2008), while
promoter variation resulting in alterations of nuclear hor-
mone receptor trans-activation may influence blood pres-
sure (Chen et al. 2008a).
Conclusion and Perspectives
Thus, common genetic variation across the human CHGA
locus is associated with cardio-renal disease traits as well
1398 Cell Mol Neurobiol (2010) 30:1395–1400
123
as their precursor (or ‘intermediate’’) phenotypes. The
associated variants are functional when tested in cellular
systems. Such findings may lead to novel approaches to the
pathophysiology, diagnosis, and treatment of the auto-
nomic dysfunction predisposing to such disease traits.
Open Access This article is distributed under the terms of the
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    • "For example, increased levels of immunoreactive CgA have been observed in a subpopulation of patients with non-small cell lung cancer lacking neuroendocrine cells in tumor tissues and in cancer patients treated with proton pump inhibitors, a class of drugs commonly used to treat acid peptic disorders [8][9][10][11]. Furthermore, elevated serum levels of CgA have been observed in patients with renal failure, heart failure, hypertension, rheumatoid arthritis, atrophic gastritis, inflammatory bowel disease, sepsis and other inflammatory diseases [1, 2, 8,[12][13][14][15][16][17][18][19][20][21][22][23]. Using specific assays, we recently observed that CgA is present in the blood of normal subjects and cancer patients as a mixture of full-length protein and fragments, including the N-terminal fragment CgA 1-76 (vasostatin-1) and other fragments lacking part or the entire C-terminal region [24, 25] . "
    [Show abstract] [Hide abstract] ABSTRACT: Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves. Tumor growth inhibition was associated with reduction of microvessel density and blood flow in neoplastic tissues. Neutralization of endogenous CgA with antibodies against its C-terminal region (residues 410-439) promoted tumor growth. Structure-function studies showed that the C-terminal region of CgA contains a bioactive site and that cleavage of this region causes a marked loss of anti-angiogenic and anti-tumor potency. Mechanistic studies showed that full-length CgA could induce, with a U-shaped dose-response curve, the production of protease nexin-1 in endothelial cells, a serine protease inhibitor endowed of anti-angiogenic activity. Gene silencing or neutralization of protease nexin-1 with specific antibodies abolished both anti-angiogenic and anti-tumor effects of CgA. These results suggest that circulating full-length CgA is an important inhibitor of angiogenesis and tumor growth, and that cleavage of its C-terminal region markedly reduces its activity. Pathophysiological changes in CgA blood levels and/or its fragmentation might regulate disease progression in cancer patients.
    Article · Nov 2015
    • "The functions of chromogranins include vesicle sorting, production of bioactive peptides, and accumulation of soluble species inside the vesicles (Iacangelo and Eiden 1995; Taupenot et al. 2003). Naturally occurring genetic variations in the chromogranin genes were shown to be associated with systemic hypertension (Zhang et al. 2009; Chen et al. 2010). Here, the results demonstrate that in contrast to VMAT2 or to catecholamine biosynthetic enzymes, gene expression of CgA and CgB is only elevated following repeated, but not single exposure to immobilization stress. "
    [Show abstract] [Hide abstract] ABSTRACT: With acute stress, the release of adrenomedullary catecholamines is important for handling the emergency situation. However, when chronic or repeated, stress alters the allostatic load and leads to a hyperadrenergic state, resulting in the development or worsening of a wide range of diseases. To help elucidate the mechanism, we examined the effects of single and repeated immobilization stress on gene expression of components of neurosecretory vesicles in the adrenal medulla. Male Sprague-Dawley rats were exposed to immobilization stress once for 2 h (1× IMO) or daily for six consecutive days (6× IMO). Compared to unstressed controls, 1× IMO elevated gene expression of vesicular monoamine transporter 2 (VMAT2). In response to 6× IMO, not only was VMAT2 mRNA still elevated, but chromogranin A (CgA) and chromogranin B (CgB) mRNAs were also increased two to three-fold above basal levels. To investigate the possible role of the hypothalamic-pituitary-adrenal axis in the induction of VMAT2, PC12 cells were treated with the synthetic glucocorticoid dexamethasone, which was found to elevate VMAT2 mRNA expression. The findings suggest that following repeated stress, elevations of various components of neurosecretory vesicles in the adrenal can facilitate more efficient utilization of the well-characterized heightened catecholamine levels.
    Full-text · Article · Dec 2011
  • [Show abstract] [Hide abstract] ABSTRACT: Chromogranin A (CgA) is the major soluble protein co-stored and co-released with catecholamines and can function as prohromone giving rise to several bioactive peptides. This review focuses on these molecules summarizing their physiological functions, their pathogenetic implications and their recent use as biomarkers in several pathological conditions. A thorough literature search of the electronic healthcare databases MEDLINE, from January 1985 to September 2013, was conducted to identify articles and studies concerned with CgA and its processing. The search strategies utilized key-words such Chromogranin A, Vasostatin-1 and 2, Chromofungin, Chromacin, Pancreastatin, Catestatin, WE-14, Chromostatin, GE-25, Parastatin and Serpinin, and was supplemented by the screening of references from included papers and review articles. A total of 209 English-language, peer-reviewed original articles or reviews were examined. The analysis of the retrospective literature suggested that CgA and its several bioactive fragments exert a broad spectrum of regulatory activities by influencing the endocrine, the cardiovascular and the immune systems and by affecting the glucose or calcium homeostasis. Since some peptides exert similar effects, but other elicit opposite responses, the regulation of the CgA processing is critical to maintain homeostasis, whereas an unbalanced production of peptides that exert opposing effects can have a pathogenetic role in several diseases. These clinical implications entail that CgA and its derived peptides are now used as diagnostic and prognostic markers or to monitor the response to pharmacological intervention not only in endocrine tumours, but also in cardiovascular, inflammatory and neuropsychiatric diseases.
    Full-text · Article · Mar 2014
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