Vol. 281, Issue 4, L749-L761, October 2001
INVITED REVIEW
Regulation of apoptosis by vasoactive peptides
Gerasimos S.
Filippatos1,
Nupur
Gangopadhyay2,
Omosalewa
Lalude3,
Narayanan
Parameswaran2,
Sami I.
Said4,5,
William
Spielman2, and
Bruce D.
Uhal2
1 Second Division of Cardiology, Evangelismos General
Hospital, GR-11526 Athens, Greece; 2 Department of Physiology,
Michigan State University, East Lansing, Michigan 48824;
3 Division of Cardiology, MetroHealth Medical Center/Case
Western Reserve University, Cleveland, Ohio 44106;
4 Department of Medicine, University Medical Center, Stony Brook
11794; and 5 Veterans Affairs Medical Center, Northport, New
York 11772
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ABSTRACT |
Although originally discovered because of their ability to
affect hemodynamics, vasoactive peptides have been found to function in
a variety of capacities including neurotransmission, endocrine functions, and the regulation of cell proliferation. A growing body of
evidence describes the ability of vasoactive peptides to regulate cell
death by apoptosis in either a positive or negative fashion
depending on the peptide and the type of target cell. The available
evidence to date is strongest for the peptides endothelin, angiotensin
II, vasoactive intestinal peptide, atrial natriuretic peptide, and
adrenomedullin. Each of these peptides is discussed, with specific
regard to apoptosis, in terms of regulatory activity, target
cell specificity, and potential role in pulmonary physiology.
programmed cell death; blood pressure; pulmonary pathophysiology; hypertension; lung fibrosis
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INTRODUCTION |
THE VASOACTIVE PEPTIDES were
discovered primarily on the basis of their effects on hemodynamics, but
the physiological roles of these molecules are now known to extend far
beyond the control of vessel tone. The observations many years ago, for
example, that angiotensin (ANG) and vasoactive intestinal peptide (VIP) were present in neurons (18, 53) led rapidly to the
concept that these and other peptides function in neurotransmission
(76). This is but one of the many roles that the
vasoactive peptides play outside the vasculature to control a variety
of processes under both normal and pathological conditions.
As investigations of the in vivo activities of vasoactive peptides were
expanded, evidence suggested that some of the peptides might function
as regulators of cell proliferation and/or death in a variety of
tissues and cell types. Among these, the roles of ANG and endothelin
(ET) in mitogenesis by cardiac fibroblasts and smooth muscle cells,
respectively, have been well documented (5, 87). More
recently, a growing body of evidence indicates important roles for some
vasoactive peptides in the regulation of apoptosis as either a
positive or negative regulator depending on the peptide. The evidence
to date for the regulation of apoptosis is most strong for ANG,
VIP, ET, atrial natriuretic peptide (ANP), and adrenomedullin (AM),
each of which is discussed below. For those peptides studied more
frequently, the present discussion is limited to cell types of the
lung, in particular, vascular endothelial cells, vascular smooth muscle
cells (VSMCs), alveolar epithelial cells (AECs), fibroblasts, and
certain leukocytes.
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APOPTOSIS AND ET |
ET-1 is a vasoconstrictor and growth factor for several cell
types, including smooth muscle cells (126, 128). It acts
through two G protein-coupled receptor subtypes termed ETA
and ETB. VSMCs mainly express ETA receptors
that mediate contraction, whereas endothelial cells express
ETB receptors that mediate vasodilation via nitric oxide generation.
It has been suggested that ET-1 plays an important role in disorders of
cell growth, and ET receptor antagonists can prevent ventricular
remodeling and postangioplasty neointima formation (17,
88). On the basis that ET-1 inhibits the growth of hepatic Ito
cells through activation of ETB receptors
(55), Wu-Wong et al. (125)
hypothesized that ET-1 might regulate apoptosis in human smooth
muscle cells. These authors induced apoptosis in human
pericardial and prostatic smooth muscle cells with the antineoplastic
agent paclitaxel, and in both types of cells, ET-1 inhibited
apoptosis. The apoptosis was dose dependent, with an EC50 of 1 nM, and was abolished by A-127722, an antagonist
selective for the ETA receptor. ET-3 and ANG II had no
effect on the apoptosis induced by paclitaxel
(125).
Antiapoptotic roles of ET.
Shichiri et al. have shown that ET-1 is a survival factor for
fibroblasts (98) and endothelial cells (97),
an effect that was also mediated by the ETA receptor via
mitogen-activated protein kinase (MAPK) activation. In fibroblast cell
lines, serum deprivation induced c-Myc-dependent apoptosis that
was reduced by ET-1 at concentrations lower than those required for
stimulation of DNA synthesis. The protective effect was mediated by the
ETA receptor; the ETA receptor antagonist
BQ-123 completely blocked the survival effect, but the ETB
receptor antagonist BQ-788 did not. Pretreatment with the inhibitor of
MAPK kinase, PD-98059, or antisense oligonucleotides against the
translation initiation site of rat p42/p44 MAPK mRNA antagonized the
survival effect of ET-1 as did transfection of the cells with a
dominant negative form of MAPK kinase (MAPKK1 S222A). Together, these
data suggested that the MAPK pathway plays a central role in cell
survival in response to ET-1.
Related work has shown that ET-1 also modulates apoptosis of
rat VSMCs. ET-1 antagonized VSMC apoptosis induced by serum
deprivation and nitric oxide; this antiapoptotic effect also was
mediated by the ETA receptor through the MAPK pathway
(99). A central role for extracellular signal-regulated
kinase (ERK) 1/2 as the downstream mediator for the antiapoptotic
effect of ET-1 has recently been demonstrated by Wu-Wong et al.
(127). In human prostatic smooth muscle cells, ERK1/2
activity decreased and apoptosis was induced after paclitaxel
treatment or serum withdrawal, but ERK1/2 activity was maintained at
higher levels and DNA fragmentation was attenuated when ET-1 was added.
The inhibitor of ERK, PD-98059, induced apoptosis in cells
cultured in serum-supplemented medium, potentiated the apoptotic
effect of serum withdrawal, and blocked the antiapoptotic effect of
ET-1. Recently, it was shown that ET-1 has a protective effect in 
-3
fatty acid-induced apoptosis of VSMCs as evidenced by
the inhibition of caspase-3 activation and subsequent DNA fragmentation
in late-stage apoptosis (15). Cytosolic ET-1 also
prevents nuclear calcium overload in human VSMCs, protecting them from
apoptosis (4).
Investigations of the role of ET-1 in models of ischemia and
reperfusion are somewhat contradictory. In a model of myocardial stunning, Klainguti et al. (47) have shown that myocardial
ET-1 is increased after 20 min of ischemia and have suggested
that ET-1 might play a role as an inducer of apoptosis. In
agreement with that theory, Shaw et al. (94) have shown
that treatment with the ETA/ETB receptor
antagonist SB-209670 could reduce the level of apoptosis
observed in the lung after ischemia-reperfusion injury in dogs
subjected to left lung allotransplantation. Notably, the cells
undergoing apoptosis were in the airway epithelium and parenchyma, suggesting that ET-1 might be proapoptotic for
epithelial cells but antiapoptotic for smooth muscle cells.
Regardless, the protective effect of ET-1 on apoptosis was also
shown in the aorta by Sharifi and Schiffrin (93)
in deoxycorticosterone acetate-salt hypertensive rats; treatment with
ETA receptor antagonists increased the rate of
apoptosis and decreased aortic cross-sectional area. A possible
role for the ETB receptor in the protective effects of ET-1
was examined in endothelial cells by Shichiri et al. (96), who showed that ET also suppressed apoptosis of rat aortic
endothelial cells in response to serum deprivation. Moreover, the
ETB receptor antagonist BQ-788 and the nonselective
ETA/ETB receptor antagonists (TAK-044 and
PD-145065) enhanced apoptosis caused by serum deprivation, but
the ETB receptor agonist BQ-3020 decreased the
apoptotic index in a dose-dependent manner.
Proapoptotic roles of ET.
However, there are other instances in which ET-1 may be
proapoptotic as well as antiapoptotic. Cattaruzza et al.
(8) have shown that ET-1 and cyclic strain of VSMCs induce
apoptosis that appeared to be ETB receptor
mediated; ET-1 (10 nM) promoted apoptosis that was completely
suppressed by the ETB receptor antagonist BQ-788 but not by
the ETA receptor antagonist BQ-123. Moreover, VSMCs derived
from homozygous spotting lethal rats, which lack a functional
ETB receptor, showed no signs of apoptosis after exposure to cyclic strain and exogenous ET-1. These results were confirmed in an experimental model in which segments of rabbit carotid
artery were subjected to increased intraluminal pressure (49). PreproET-1 mRNA and ET-1 were upregulated
predominantly in endothelial cells, and the ETB receptor in
smooth muscle cells was significantly increased. An increase in
apoptosis in the media of the carotid arteries was detected
when arterial segments were exposed to a perfusion pressure of 160 mmHg
for 6 h. The pressure-induced increase in apoptosis was
prevented by the ETB receptor antagonist BQ-788 but not by
the ETA receptor antagonist BQ-123 (49).
ET-1 may also play a role in the pathophysiology of cancers; it
has been suggested that ET-1 is associated with prostate cancer because
ET-1 is increased in patients with advanced stages of the disease
(68, 95). Rat and human colon carcinoma cell lines express
Fas and Fas ligand, but these cells are resistant to Fas-induced apoptosis; because ET-1 is implicated as a growth factor in
some cell types, Eberl et al. (20) examined the role of
ET-1 in cancer cell resistance to apoptosis in response to Fas
ligand. The mixed ETA/ETB receptor antagonist
bosentan potentiated Fas-induced apoptosis, but low
concentrations of exogenous ET-1 (10
13 to
1010 M) antagonized the bosentan-induced
apoptosis. At higher concentrations (108 to
107 M), the protective effect of ET-1 was absent.
In colon carcinoma cells that express only ETA receptors,
the ETA receptor antagonist BQ-123 and the protein kinase
(PK) C inhibitor bisindolylmaleimide IX could induce apoptosis,
but the ETB receptor-specific antagonist BQ-788 had no
effect (19). Egidy et al. (21) found that in
human glioblastoma, ETA receptors were highly expressed in
glioblastoma vessels, whereas ETB receptors were found
mainly in the tumor cells. Those findings were interpreted to suggest
that glioblastoma vessels might be a source of ET-1 that acts on cancer
cells via the ETB receptor. The possibility that a similar
mechanism might be active in cancers of the lung has not been evaluated.
In A375 human melanoma cells, ET-1 induced apoptosis and
nuclear accumulation of p53 (70). These effects appeared
to be mediated by the ETB receptor because the ratio of
ETA to ETB receptors was 1:4. On the basis of
this and related works discussed above, the relative abundance of
ETA versus ETB receptors expressed by individual cell types is believed to be important for the control of
apoptosis. Regardless, the influence of ET-1 on the regulation of apoptosis may have important clinical implications.
Imbalanced proliferation and apoptosis are important in tumor
progression, in cardiac remodeling, in the pathogenesis of vascular
hypertrophy in hypertension, and in restenosis of arteries. Whether
ET-1 induces or suppresses apoptosis appears to depend on cell
type and the cell-specific expression of ETA versus
ETB receptor subtypes; a summary of the available data to
date is presented in Fig. 1. The
potential roles of ET-1 and its receptors in the control of lung cell
apoptosis are yet to be evaluated.
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Fig. 1.
Role of endothelin (ET)-1 in the regulation of
apoptosis. In fibroblasts and vascular smooth muscle cells
(SMCs), activation of ET receptor type B (ETB), as occurs
in cyclic strain and at high vascular perfusion pressure, activates
apoptosis (solid lines) in a manner inhibitable by
ETB receptor-selective antagonists BQ-788, TAK-044, and
PD-145065 (dotted lines). In the same cells, apoptosis in
response to serum deprivation, paclitaxel, or nitric oxide (NO) is
blocked by activation of ETA receptor, an effect that is
mediated through mitogen-activated protein kinase (MAPK) and is
inhibitable by ETA receptor-selective antagonists A-127722
and BQ-123. Activation of ETB receptor also induces
apoptosis in A375 carcinoma cells and lung epithelial cells
during ischemia-reperfusion. In contrast, in endothelial and
colon carcinoma cells, activation of ETB receptor blocks
apoptosis in response to serum deprivation or Fas-Fas ligand
(FasL) interaction; in either case, the inhibition is prevented by
ETB receptor-selective antagonists (dotted lines). See text
for details.
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APOPTOSIS AND ANP |
In 1981, de Bold et al. (11) observed that infusion
of extracts of atrial tissue into rats caused a copious natriuresis. These observations led to the isolation and cloning of ANP, the first
member of a family of peptides with potent natriuretic, diuretic, and
vasorelaxant activity (41). It is produced primarily in
the cardiac atria, mainly in response to increased atrial wall tension
as a result of increased intravascular volume. Several hormones and
neurotransmitters such as ET, arginine, vasopressin, and catecholamines
directly stimulate the secretion of ANP. Urodilatin [ANP-(95-126)] is the product of alternative
ANP gene expression in the kidney (51). Brain natriuretic
peptide (BNP), although found in the human brain, is predominant in
cardiac ventricles (67). C-type natriuretic peptide (CNP),
which possesses vasorelaxant activity but is not natriuretic, is found
primarily in the brain and also in the anterior pituitary, the kidney,
vascular endothelial cells, and, at low levels, plasma
(102).
Three natriuretic peptide receptors (NPR-A, NPR-B, and NPR-C) have been
identified in mammalian tissues (48). NPR-A and NPR-B are
linked to the cGMP-dependent signaling cascade and mediate most of the
cardiovascular and renal effects of the ANPs. NPR-C is thought to be
involved in the clearance of the peptides (54). In
general, the natriuretic peptides defend against salt and water retention, inhibit the production and action of vasoconstrictor peptides, promote vascular relaxation, and inhibit sympathetic outflow.
These peptides have also been shown to possess antimitogenic activity
in the cardiovascular and other organ systems (28, 36,
104). Their role in the regulation of apoptosis has been described mainly in the cardiovascular system.
ANP and apoptosis of cardiac myocytes.
Myocardial hypertrophy occurs early in the clinical course of heart
failure and is an important risk factor for subsequent cardiac
morbidity and mortality. Induction of the natriuretic peptide genes is
a feature of cardiac hypertrophy in all mammalian species and is a
prognostic indicator of clinical severity. Loss of cardiac myocytes as
a result of apoptosis has been reported in both experimental
and clinical cardiac hypertrophy (35). Increased local
levels of ANP may promote the transition from myocardial hypertrophy to
heart failure by inducing apoptotic cell loss (31).
Apoptotic cell loss has been well demonstrated in failing human
hearts (22, 71). Wu et al. (124) examined the
effect of ANP on neonatal rat cardiac myocytes. ANP induced apoptosis in a manner that was dose dependent and mediated by NPR-A and NPR-B, both of which are coupled to the generation of cGMP.
That study (124) also showed that apoptosis in
response to ANP was myocyte specific and did not occur in fibroblasts
and smooth muscle cells despite similar expression patterns of all three isoforms of NPRs in the three cell types. The apoptosis was antagonized by norepinephrine-induced increases in cAMP.
Furthermore, ANP inhibited the expression of Mcl-1, an
antiapoptotic homolog of Bcl-2. During embryonic development,
the ANP gene is expressed in both the atrium and ventricle, but its
expression is downregulated in the ventricle shortly after birth.
During the progression of heart hypertrophy and, in particular, the
transition from hypertrophy to failure, reexpression of ANP in myocytes
occurs in the left ventricle (130). The abundance of mRNA
for ANP in the left ventricle is thus an important index of this transition.
The recent study by Kang et al. (39) showed that copper
deficiency in mice induced a cardiac hypertrophy that was progressive over time and was associated with myocardial cellular
apoptosis. That investigation also showed that copper
deficiency caused a significant elevation in cardiac ANP mRNA and that
this elevation was markedly depressed in the hearts of
metallothionein-transgenic mice. The study also showed that ANP induced
apoptosis in cardiac myocytes in a dose- and time-dependent
fashion and that metallothionein-transgenic cardiomyocytes were
significantly resistant to the ANP-induced apoptosis.
ANP and apoptosis of endothelial smooth muscle cells and
VSMCs.
Several studies have shown that ANP and CNP (36, 78) as
well as other cGMP-elevating agents such as nitric oxide, sodium nitroprusside, and the cGMP mimetic 8-bromo-cGMP (77, 131) inhibit vascular smooth muscle hypertrophy and proliferation.
ANP has also been shown to be antimitogenic in cardiac myocytes and
fibroblasts (7). The vascular structure is thought to be
maintained by the countervailing balance between growth-promoting vasoconstrictive antiapoptotic factors and growth-inhibiting
vasodilatory proapoptotic factors. Just as growth promoters can
prevent apoptosis, Trindade et al. (107)
hypothesized that growth inhibitors might induce apoptosis.
Consistent with this hypothesis, exposure of rabbit aortic VSMCs to ANP
or CNP (108 to 106 M) dose dependently
increased apoptosis, with a maximal stimulation of over
threefold. This effect was shown to be mediated by the cGMP-linked
receptors NPR-A and NPR-B. These and other aspects of the signaling of
apoptosis are summarized in Fig.
2.
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Fig. 2.
Signaling of apoptosis in response to atrial natriuretic
peptides (ANPs). Pathological conditions including congestive heart
failure, myocardial infarction, and shock result in increased plasma
and tissue ANP and other peptides including brain natriuretic peptide
(BNP) and C-type natriuretic peptide (CNP). These can induce
apoptosis in target cells of the heart and vasculature that
express the natriuretic peptide receptor (NPR)-A or NPR-B, both of
which act through increased cGMP. In cardiac myocytes, the
apoptotic response to ANPs can be inhibited ( ) by metallothionein
(MT) or norepinephrine. In vascular SMCs (VSMCs) or endothelial cells
(ECs) of the rat, the apoptotic response to ANP can be inhibited by
ET-1, HS-142-1 (a selective antagonist of NPR-A or NPR-B), or KT-5823
(an inhibitor of cGMP-dependent kinases). See text for details.
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In a more recent study, Suenobu et al. (103) demonstrated
that ANP, BNP, and CNP dose dependently induced apoptosis of
rat endothelial cells with equal potency. ANP-induced apoptosis
was blocked by a natriuretic peptide receptor antagonist (HS-142-1) that selectively antagonizes NPR-A and NPR-B (62); it was
also blocked by a selective inhibitor of cGMP-dependent kinase
(KT-5823) and by the vasoconstrictor ET-1 but not by a selective
inhibitor of soluble guanylyl cyclase
(1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one). In the same study, pretreatment of endothelial cells caused a marked
accumulation of the tumor suppressor gene product p53, whereas the B
cell leukemia/lymphoma gene product Bcl-2 was not affected. The
physiological and pathophysiological relevance of these in vitro data,
however, remains uncertain because supraphysiological concentrations of
natriuretic peptides were used. It is possible that supraphysiological
concentrations could act on the vascular endothelium under certain
pathological conditions such as congestive heart failure
(30), myocardial infarction (63), and septic shock (30).
The available data to date suggest that ANP may be important in the
transition from myocardial hypertrophy to heart failure through its
ability to induce myocyte apoptosis. It is possible, therefore,
that drugs that counter the effects of ANP on apoptosis may be
useful in the treatment of heart failure. With regard to the
vasculature, the countervailing balance between endothelium-derived vasodilators and vasoconstrictors may determine endothelial cell and
VSMC apoptosis and survival, which, in turn, may contribute to
the development and/or progression of vascular pathology. The regulation of apoptosis by natriuretic peptides may thus play an important role in vascular remodeling during atherosclerosis, angiogenesis, and hypertension.
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APOPTOSIS AND AM |
Since the discovery and initial isolation of AM from
pheochromocytoma, a role has been suggested for this peptide in
important biological processes such as cell proliferation and
apoptosis. Nevertheless, the first biological responses
observed for AM were potent hypotensive and vasodilatory effects and
the ability to raise intracellular cAMP (45, 46, 91).
Human AM is a 52-amino acid peptide with a single disulfide bridge
between residues 16 and 21 and with an amidated tyrosine carboxy
terminus (45, 46). It shows some homology with
calcitonin gene-related peptide (CGRP) and is therefore considered a
member of the calcitonin, CGRP, amylin peptide family (64,
123). AM is synthesized as part of a larger precursor molecule
termed preproAM. In humans, this precursor consists of 185 amino acids.
PreproAM contains a 21-amino acid NH2-terminal signal
peptide that immediately precedes a 20-amino acid amidated peptide
designated proAM NH2-terminal 20 peptide (45,
46). For a discussion of the many biological actions of proAM
NH2-terminal 20 peptide, the reader is referred to an excellent review by Samson (90).
AM and CGRP not only belong to the same family of peptides, they also
interact with the same receptor. Recent studies have suggested that AM
and CGRP both interact with calcitonin receptor-like receptor, which
was originally designated as the CGRP receptor. The interaction and
affinity of these two ligands to this receptor are regulated by the
expression of accessory proteins called receptor activity-modifying
proteins (RAMPs) (58). The expression of RAMP-1, RAMP-2,
and RAMP-3 affects the affinity of the calcitonin receptor to
calcitonin and amylin and that of the calcitonin receptor-like receptor
to AM and CGRP (6, 50, 58, 65, 107). This review focuses
entirely on the role of AM in apoptosis, and readers are therefore referred to the review by Foord and Marshall
(25) for a more complete discussion of RAMPs and their
known functions.
The gene encoding preproAM is termed the AM gene and has been mapped
and localized to a single locus on chromosome 11. The AM gene is
expressed in a wide range of tissues. Evidence from both
immunocytochemistry and cultured cell lines reveals that AM is
expressed by many different cell types including vascular endothelial
cells (32). In addition, many tumor cell lines express the
AM mRNA and/or immunoreactive peptide (60). The normal
plasma concentration of AM is in the range of 1-10 pM, with most
values between 2 and 3.5 pM. In many cardiovascular, renal, and
respiratory disorders, plasma AM has been reported to be elevated,
suggesting that AM may be a component of the regulation of hemodynamics
and might be released to compensate for elevated blood pressure
(32).
Antiapoptotic and proapoptotic roles of AM.
Since the initial discovery of AM in a tumor (40)
the effects of AM on tumor cell lines and other cell types have been
widely reported (89). AM has been suggested to be a growth
factor for several tumor cell lines including lung tumor cells
(60). Antibodies against AM were shown to inhibit the
growth of some tumor cells, suggesting that autocrine synthesis of AM
confers growth-promoting activity (60). Furthermore, AM
has been demonstrated to protect vascular endothelial cells from
apoptosis, suggesting a cell survival role for AM in the
vasculature (43). A role for AM in the growth of
endothelial cells in vivo is also suggested by AM gene knockout mice.
The knockout is embryonically lethal due to the absence of placental
vascularization (100). Although it is generally thought to
promote cell proliferation and to be a survival factor for tumor and
endothelial cells, respectively, AM is antiproliferative for VSMCs and
glomerular mesangial cells. In addition, Parameswaran et al.
(72) and others (42, 59) have shown
that AM can induce apoptosis in glomerular mesangial cells.
Signaling of apoptosis by AM.
Mechanisms believed to be involved in the signaling of
apoptosis by AM are summarized in Fig.
3. cAMP has been shown to be the second
messenger for the AM-sensitive receptor in most systems tested to date.
However, some of the effects of AM on cell survival, such as the
protective effect on endothelial cells, have been shown to be
independent of cAMP. Agents capable of elevating or mimicking cAMP,
such as forskolin or dibutyryl cAMP, had no effect on apoptosis
in endothelial cells, and cAMP antagonists did not affect AM-mediated
cell survival (43, 92). In glomerular mesangial cells,
however, cAMP and its activators can induce apoptosis
(65). Furthermore, AM-induced apoptosis in
mesangial cells appears to be dependent on cAMP because a PKA inhibitor
could block apoptosis in response to AM (72). Thus
the signaling of apoptosis or cell survival by AM appears to be
cAMP dependent in renal mesangial cells but cAMP independent in some
endothelial cell types.
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Fig. 3.
Signaling pathways of
adrenomedullin (AM) action on apoptosis by mesangial and
endothelial cells. AM activates apoptosis in mesangial cells
(left, solid arrows) but protects against apoptosis
of endothelial cells (right, dotted arrows). AM-induced
apoptosis of mesangial cells is mediated by cAMP-dependent
protein kinase (PK) A. Activation of cAMP-PKA, p38-MAPK, and protein
phosphatase 2A (PP2A) is necessary for AM-induced apoptosis.
Caspase-3 and caspase-8 activation in response to AM has also been
observed. However, the interaction of the caspase pathways with that of
MAPK is not currently understood. The protective effect of AM on
endothelial cells is independent of cAMP-PKA and cGMP-PKG but is
dependent on NO. The receptor complex with which AM interacts in both
cell types is represented by a 7-transmembrane-domain G protein-coupled
receptor that associates with a single transmembrane receptor
activity-modifying protein (RAMP) (106). ERK,
extracellular signal-regulated kinase. See text for details.
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Definition of the mechanisms by which AM mediates antiapoptotic
versus proapoptotic signaling requires further investigation. Although the antiapoptotic effect of AM on endothelial cells is not
mediated by either cAMP or cGMP, evidence suggests that nitric oxide
may be a mediator of AM-induced cell survival. AM and nitric oxide
induced an antiapoptotic effect in endothelial cells through a
cGMP-independent mechanism (92) despite the fact that cGMP is a downstream target for nitric oxide in other cell types. In 1999, Shichiri et al. (96) showed that the antiapoptotic
action of AM on endothelial cells was mediated through the induction of
the antiapoptotic gene max.
In contrast, renal mesangial cell apoptosis in response to AM
is dependent on cAMP-PKA activation (66). AM-stimulated
apoptosis also is accompanied by activation of caspase-8
and caspase-3 (66, 73); caspase-8 is activated as early as
8 h after treatment, whereas caspase-3 activation reaches a peak
by 16 h. AM also activates the c-Jun NH2-terminal
kinase (JNK) and p38 MAPK pathways in mesangial cells as well as the
activity of protein phosphatase 2A (PP2A) (22, 74). This
occurs in conjunction with inhibition of the ERK pathway, which is
mediated through the increase in PP2A activity (74).
Activation of p38 and PP2A appears to be important in the stimulation
of apoptosis because the p38 inhibitor SB-203580 or the PP2A
inhibitor okadaic acid could block AM-induced apoptosis (74, 75). The role of the JNK pathway in this process is
still unclear as is the possible interaction of the MAPK and
caspase-mediated pathways in AM-stimulated apoptosis.
The physiological significance of the antiapoptotic or
proapoptotic effects of AM remains to be determined. With regard to endothelial cells, it is hypothesized that the marked increase in AM in
various pathological states may function to defend the vascular lining
cells from injurious agents in an autocrine or paracrine manner. In
light of the knowledge that aberrant proliferation of glomerular
mesangial cells is an important event in glomerular disease,
AM-stimulated apoptosis of these cells, also in an autocrine or
paracrine manner, may serve to hinder pathogenesis. In both instances,
although the biological response to AM may be quite different, it is
possible that AM could play the beneficial role of retarding disease progression.
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REGULATION OF APOPTOSIS BY VIP AND RELATED PEPTIDES |
Evidence relating to the regulation of apoptosis by VIP
and similar peptides is derived from studies of apoptosis of
lung parenchymal cells in the course of acute lung injury, of activated T lymphocytes (83) and of neuronal cells subjected to
certain neurotoxic agents or trophic deprivation.
VIP and lung injury.
After the demonstration that VIP could reduce or prevent lung injury in
experimental models of acute respiratory distress syndrome (ARDS), Said
and associates (84-86) examined the possibility that
this peptide may exert its protective effect, in part, by modulating
apoptotic cell death. First, it was necessary to show whether apoptosis was indeed an important pathogenic mechanism in these models of lung injury. This appeared to be the case based on
three lines of evidence (85). First, the activity of
caspase-3, a key effector of apoptosis, was increased in lungs
injured by excitotoxicity, i.e., by overactivation of the
N-methyl-D-aspartate subtype of glutamate
receptors (86). Second, the inhibition of caspase activity
by selective caspase inhibitors prevented or attenuated this injury.
Third, lung injury was associated with downregulation of the
antiapoptotic protooncogene bcl-2 (80) in lungs
injured by N-methyl-D-aspartate or by oxidative
stress due to the prooxidant herbicide paraquat or to xanthine oxidase.
Having demonstrated that apoptosis contributes importantly to
cell death in these models of lung injury, the same investigators (85) then evaluated the antiapoptotic
activity of VIP and its contribution to the prevention or attenuation
of acute edematous lung injury. These studies revealed that the
reduction in lung injury by VIP was associated with the inhibition of
caspase activation and the upregulation of bcl-2, both of which
suppress cell death and promote cell survival (26,
85).
Cell types protected by VIP.
The basis for the high-permeability edema of ARDS is a loss of
alveolar-microvascular barrier function (121). In
assessing the importance and regulation of apoptosis in ARDS,
therefore, it is useful to examine apoptotic and antiapoptotic
events in AEC and pulmonary endothelial cell preparations.
Morphological and ultrastructural features of apoptosis were
observed in pulmonary endothelium as a part of acute lung injury
induced by endotoxin lipopolysaccharide in mice (27). In
primary cultures of rat AECs and the corresponding human cell line
A549, apoptosis has been induced by tumor necrosis factor
(TNF)-
(114), Fas ligand (118), ANG II
(119), the antineoplastic drug bleomycin (29, 115), and the antiarrhythmic drug amiodarone (2).
VIP, tested in the first three of these experimental models, dose
dependently inhibited apoptosis (110).
Soluble Fas ligand was present in the bronchoalveolar lavage (BAL)
fluid of patients with severe ARDS, and this BAL fluid induced
apoptosis of primary human distal lung epithelial cells (57). BAL fluid from ARDS patients, however, had an
antiapoptotic effect on neutrophils (56). Widespread,
caspase-3-dependent apoptosis of lymphocytes was detected in
patients dying of sepsis and multiorgan dysfunction (3)
and possibly contributed to the impairment of the immune response
(34). The possible modification of apoptosis by
VIP in these settings has not been tested.
VIP and the related pituitary adenylate cyclase-activating peptide
(PACAP) have been shown to exert major modulatory influences on
multiple aspects of the immune response (79). One recently reported action relates to activation-induced apoptosis of T
lymphocytes, a process that is mediated through Fas-Fas ligand
interactions (12). Both VIP and PACAP inhibit
activation-induced apoptosis of T lymphocytes in vitro and in
vivo, largely due to peptide-induced reduction of Fas ligand expression
(12). The inhibition was dependent on specific VIP/PACAP
receptors VPAC, and VPAC2 but not VPAC1. Through this action,
VIP and PACAP might allow the survival of a small number of activated T
cells to differentiate into memory cells. Furthermore, by inhibiting
this form of cell-mediated cytotoxicity, the peptides might protect
against the cell death of bystander targets that occurs in autoimmune
and inflammatory diseases (12).
Said (82) has found that VIP and PACAP protect a
variety of neural cells against apoptotic death and promote their
survival. Such protection has been demonstrated for both peptides
against glutamate toxicity of cerebral cortical neurons and neuronally differentiated pheochromocytoma (PC12) cells (86) and
against apoptotic PC12 cell death due to trophic support withdrawal
(14). PACAP protects developing and mature
cerebellar granule neurons against apoptotic cell death
(112). The neuroprotective effects of VIP and PACAP (see
Fig. 4) are mediated, at least in part, via activation of PKA through PKC (112) and cAMP response
element binding protein phosphorylation (113). The
effector mechanisms include inhibition of caspase-3 activity
(13) upregulation of bcl-2, and suppression of cytoplasmic
cytochrome c translocation (Antonawich F and Said SI,
unpublished observations).
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Fig. 4.
Cell survival pathways involving vasoactive intestinal
peptide (VIP) and pituitary adenylate cyclase-activating peptide
(PACAP). VIP and PACAP promote cell survival largely via activation of
adenylate cyclase (AC)-dependent PKA (VIP and PACAP-27) and PKC
(PACAP-38). MAPK is also activated. The reactions culminate in
activation of cAMP response element binding protein (CREB) via its
phosphorylation, followed by upregulation of the antiapoptotic
protooncogene Bcl-2. PLC, phospholipase C; P,
phosphorylation. [Reproduced with permission from Said and Dickman
(85).]
|
|
The ability of VIP and related peptides to inhibit apoptosis
induced by different means and involving diverse mechanisms and pathways suggests a role for these peptides as physiological modulators of programmed cell death. As pharmacological agents, the peptides may
have potential therapeutic value in limiting or preventing cell injury
and death in the lung, brain, heart (38), and other vital organs.
| |
REGULATION OF APOPTOSIS BY ANG II |
Investigations of the long-term effect of inhibitors of
ANG-converting enzyme (ACE) on cardiac and other tissues revealed that
ACE inhibitors have a significant influence on cardiac remodeling (105). In light of the knowledge that tissue remodeling
involves a coordinated interplay between cell proliferation and death, those findings led to the hypothesis that ANG might be a regulator of
cell death by apoptosis. That theory was proved correct by the
discovery that ANG II is a potent inducer of apoptosis in freshly isolated primary cultures of cardiac myocytes (9,
37). In subsequent years, this concept was confirmed both in
vitro and in vivo through a variety of studies that now comprise a
significant body of literature (reviewed in Ref. 23). This
discussion, however, focuses on cells of the lung, in particular cells
of the capillary endothelium and alveolar epithelium and lung myofibroblasts.
ANG II and endothelial cells.
Capillary endothelial cells are considered the most important producers
of circulating ANG II by virtue of the ACE activity in the lumen of the
pulmonary vascular bed (69, 81). On the other hand,
endothelial cells also are known to undergo apoptosis in
response to ANG II, albeit at concentrations significantly higher than
the normal plasma ANG II level. In a study of cultured human umbilical
vein endothelial cells, Dimmeler et al. (16) showed that
purified ANG II could induce apoptosis, with an
EC50 of 100 nM, a concentration well above the normal
plasma ANG II concentration of 5-8 pM (1). The
apoptosis could be prevented by simultaneous blockade of the
ANG receptor subtypes 1 and 2 (AT1 and AT2,
respectively). An investigation (52) in cultured human
coronary artery endothelial cells demonstrated that ANG II could
potentiate apoptosis induced by TNF- and experimental anoxia-reoxygenation. In that study, apoptosis was blocked by losartan, which suggested that AT1 was the ANG receptor
subtype active in mediating this response.
To date, the effect of ANG II on apoptosis has not yet been
determined with primary cultures of well-differentiated pulmonary microvascular endothelial cells. Thus the possibility exists that lung
endothelial cells in vivo respond differently to ANG II than the human
umbilical vein endothelial cell or human coronary artery endothelial
cell lines. On the other hand, the EC50 for induction of
apoptosis in these cell lines is far above the plasma ANG II concentration, at least under normal conditions. Whether or not the
significantly elevated plasma ANG II levels attained in ARDS (122) or other lung injury settings are within a range
capable of inducing pulmonary endothelial cell death is an interesting topic for future inquiry.
ANGII and epithelial cells.
More recent evidence indicates that several extravascular cell types of
the lung undergo apoptosis in response to ANG II at significantly lower concentrations and also have the capacity for
inducible expression of ANG II in response to toxins. In 1999, Wang et
al. (115) found that ANG II was a potent inducer of
apoptosis in AECs, which exhibit an EC50 for ANG II
of ~10 nM. Although this concentration is still higher than the
normal plasma ANG II level of ~10 pM (1), measurement of
the extravascular or interstitial ANG II concentration found it to be
as much as 100-fold higher than that in plasma, at least in the heart
(111) and eye (10). Although the
extravascular ANG II concentration in lung is unknown, plasma and lung
tissue ANG II levels are known to increase in lung injury (101,
122).
More importantly, subsequent studies found that endogenous or
xenobiotic toxins can evoke an autocrine synthesis of ANG II by AECs.
Wang et al. (118) in 1999 found that activation of Fas (APO1, CD95), a receptor previously shown to be expressed and functional in AECs for the induction of apoptosis in vivo
(24), stimulates AECs to synthesize ANG II de novo.
Moreover, the autocrine synthesis of ANG II was found to be required
for the induction of apoptosis by Fas; the apoptosis
could be abrogated by ANG receptor antagonists or other blockers of ANG
II function (118). This finding provided a mechanism for
the earlier observation that the prototype ACE inhibitor captopril was
a potent blocker of apoptosis in the AEC-derived cell line A549
independent of its thiol moiety (108).
Autocrine generation of ANG II is also required for the apoptotic
death of AECs in response to TNF-, a toxin capable of reducing AEC
number in primary culture by >50% over 40 h of exposure
(114). Both the induction of apoptosis and the net
decrease in cell number could be abrogated by an ANG receptor
antagonist, by ACE inhibitors, or by antisense oligonucleotides against
angiotensinogen (ANGEN) mRNA. The ability of the same agents to prevent
apoptosis of AECs in response to the benzofuran antiarrythmic
agent amiodarone (2) or the antineoplastic agent bleomycin
(115) suggests that autocrine generation of ANG II may be
a constitutive mechanism for the signaling of apoptosis in AECs
regardless of the initiating stimulus. Moreover, the successful
blockade of bleomycin-induced apoptosis in vivo by an ACE
inhibitor (115) suggests that the same mechanism defined in primary cultures of AECs is also active in the intact animal.
Initial investigations of the ability of ANG II to induce
apoptosis in AECs revealed that AECs express both major
subtypes of the ANG II receptor, AT1 and AT2,
at least at the level of mRNA (119). A more recent study
(116), however, indicated that AEC apoptosis can
be blocked by AT1 receptor-selective antagonists but not by
AT2 receptor-selective blockers. These findings are consistent with observations from cultured human coronary artery endothelial cells (see ANG II and endothelial
cells) but are in contrast to studies of pheochromocytoma
and PC12W cell lines (33, 129), which suggested that
AT2 receptor is the mediator of apoptosis. Whether
this discrepancy is related to the use of well-differentiated primary
cell cultures versus transformed cell lines as model systems or whether
the ratio of AT1 to AT2 receptors in AECs is
modulated in various injury settings awaits further investigation.
Regardless, the finding that autocrine generation of ANG II is required
as a mediator of apoptotic cell death in the alveolar epithelium has significant implications for the therapeutic management of acute
lung injury and fibrogenesis (23).
ANG II and fibroblasts.
An additional local source of ANG II that is independent of circulating
ANG II is the myofibroblast. In the heart, cardiac myofibroblasts that
emerge after myocardial infarction are known to synthesize ANG II and
thereby influence local gene expression and apoptosis of
surrounding myocytes (44). The same phenomenon was
recently found by Wang et al. (117) to occur in
the lungs, at least in patients with some forms of fibrotic lung
disease. Primary cultures of myofibroblasts isolated from open lung
biopsy specimens from patients with fibrotic lung disorders were found to synthesize ANGEN and to convert a fraction of the proprotein to ANG
II. Although the proteolytic conversion was incomplete, primary AECs
express the converting enzymes, and thus ANGEN can induce
apoptosis of AECs as potently as ANG II (114), at
least in vitro. The possibility that the ANGEN synthesized by the
myofibroblasts affects the apoptosis and/or phenotype of the
fibroblast population itself is currently under investigation.
Together, these findings are regarded as evidence to explain the
apoptotic death of AECs in vivo that are immediately adjacent to
the foci of myofibroblasts within biopsies of fibrotic human lungs
(109). A determination of whether ACE inhibitors or ANG receptor antagonists might have a beneficial effect in patients suffering from fibrotic lung disease or other forms of lung injury will
be performed in clinical trials; the positive results of previous
experiments with several different animal models suggest that this
possibility is worthy of evaluation (61, 115, 120). The
known roles of ANG II as a regulator of apoptosis of cells in
the lung are summarized in Fig. 5.
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Fig. 5.
Regulation of apoptosis by angiotensin II (ANG II) in
the lungs. Myofibroblasts emerging in fibrotic lung tissue
(1) synthesize angiotensinogen (ANGEN), which is converted
(2) by adjacent alveolar epithelial cells (AECs) to ANG II.
Apoptosis is induced through ANG II binding to receptor subtype
1 (AT1; 3), with an EC50 of ~10 nM
in primary cultures of AECs; although the AT1 receptor is
depicted here as basolateral, the actual orientation of the receptor in
AECs is unknown. Induction of apoptosis in AECs by
FasL or tumor necrosis factor (TNF)- stimulates autocrine production
of ANGEN (4); interruption of steps 2, 3, or 4 prevents AEC apoptosis. In the
capillary, ANG II induces apoptosis of endothelial cells
(5), with an EC50 of ~100 nM, through pathways
involving both AT1 and AT2 receptor subtypes.
Endothelial cell survival is ensured by the extremely low intravascular
concentration of ANG II ([ANG II]; 6), but this rises
significantly in lung injury. The potential contribution of circulating
ANG II to the extravascular pool in the lung (7) is unknown,
but in other tissues, extravascular ANG II is as much as 100-fold
higher than that in plasma. ARDS, acute respiratory distress syndrome.
See text for details and references.
|
|
| |
SUMMARY |
As discussed above, the effects of the vasoactive peptides on the
control of apoptosis are many and varied. Early data had suggested a model in which the hemodynamic effects of a given peptide
might predict its influence on cell proliferation or death. However, as
is often the case, additional data proved that view to be overly
optimistic; although the vasodilators VIP and AM have antiapoptotic
properties, ANP is vasodilatory but appears to be generally
proapoptotic. Moreover, a given peptide can either promote or block
apoptosis depending on the cell type and likely other factors
yet to be discovered.
Among these is the possibility of "cross talk" between
proapoptotic versus antiapoptotic peptides. For example, VIP
was shown to prevent apoptosis in response to ANG II
(110) and may well be found in future studies to block the
proapoptotic stimuli of other peptides. Continued definition of the
signaling pathways evoked by the active receptors for each vasoactive
peptide will ultimately shed light on the specific mechanisms of
interaction. However, the findings that VIP and PACAP exert
antiapoptotic effects through a pathway that is dependent on cAMP
and PKA (112, 113), whereas the antiapoptotic
influence of AM on endothelial cells appears to be cAMP independent
(43, 92), offer a glimpse of the complexities likely to be encountered.
Nonetheless, the available data indicate that the control of cell death
exerted by vasoactive peptides is of sufficient power to exert
significant physiological effects in vivo (85, 86, 115).
These findings support the contention that the pharmacological manipulation of apoptosis holds great potential as a means of controlling cell population size and function as well as the
progression of disease (26, 31, 35). In some instances,
the therapeutic potential of peptide receptor antagonists, inhibitors
of peptide synthetic enzymes, or the vasoactive peptides themselves are
currently being evaluated through clinical trials. It is the hope of
all the authors that the discussion above will stimulate interest and
additional effort in this interesting and important area of research.
| |
ACKNOWLEDGEMENTS |
The research reported here was supported by National Heart, Lung,
and Blood Institute Grants HL-30450 (to S. I. Said) and HL-45136
(to B. D. Uhal) and the Department of Veterans Affairs (S. I. Said). Portions of the manuscript preparation were supported by
Evangelismos General Hospital (Athens, Greece) and the Department of
Physiology, Michigan State University (East Lansing, MI).
| |
FOOTNOTES |
Address for reprint requests and other correspondence: B. D. Uhal, Dept. of Physiology, 310 Giltner Hall, Michigan State Univ., East Lansing, MI 48824 (E-mail: uhal{at}msu.edu).
| |
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