© 2000 American Heart Association, Inc.
Editorial |
Hyperinsulinemia and Vascular Dysfunction: The Role of Nuclear Factor-
B, Yet Again
From the College of Physicians & Surgeons, Columbia University, New York, NY.
Correspondence to Dr Ann Marie Schmidt, College of Physicians & Surgeons, Columbia University, 630 W 168th St, P&S 17-501, New York, NY 10032. E-mail ams11{at}columbia.edu \ © 2000 American Heart Association, Inc.
Key Words: insulin • oxidant stress • Rho GTPases • nuclear factor-
B
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Introduction |
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 Top Introduction Activation of NF-{kappa}B: Role...Activation of NF-{kappa}B: Role...Effects of Insulin: A...Is NF-{kappa}B a Logical...References |
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Syndromes of type 2 diabetes and insulin resistance are accompanied by varying degrees of hyperinsulinemia. To date, a number of epidemiological studies have suggested that elevated levels of circulating insulin contribute independently to cardiovascular risk.1 2 It is not surprising, however, that some studies demonstrated no, or marginally increased, risk for cardiovascular complications,3 4 as it is clear that insulin is not the sole culprit. Other factors, such as hyperlipidemia and even intermittently elevated levels of blood glucose, are tightly linked to syndromes characterized by elevated levels of insulin. The key, therefore, to pinpointing the potentially adverse effects of insulin on the vessel wall concerns analysis of its effects on specific properties of vascular cells.
In this issue of Circulation Research,
Golovchenko et al5
have focused on the role of insulin in activation of the pleiotropic
transcription factor nuclear factor-B (NF-B). This is a logical
target, as evidence mounts to support a role for activation of NF-B
in the pathogenesis of
atherosclerosis,6 7
ischemia-reperfusion
injury,8 9
and
diabetes.10 11
For example, target genes of NF-B, such as tumor necrosis factor-
(TNF-) and vascular cell adhesion molecule-1, have long been
speculated to participate in the earliest stages of atherogenesis.
Indeed, RelA/p65, one of the components of NF-B, has been identified
within the nuclei of vascular smooth muscle cells (VSMCs) and
mononuclear phagocytes in human
atheromata.12 The
key question arises, therefore, what are the molecular triggers that
switch on NF-B in the vessel wall?
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Activation of NF-B: Role of AGEs
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TopIntroductionActivation of NF-{kappa}B: Role...Activation of NF-{kappa}B: Role...Effects of Insulin: A...Is NF-{kappa}B a Logical...References |
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In this context, a mixed bag of vascular-perturbing factors associated with diabetes and insulin resistance has already been linked to activation of NF-
B. For example, one
consequence of hyperglycemia is the generation of advanced glycation
end products
(AGEs).13
Interaction of these products of nonenzymatic glycation/oxidation of
proteins, with their key signal transduction receptor RAGE (receptor
for AGE), results in activation of NF-B in endothelial cells,
mononuclear phagocytes, and VSMCs, by processes that involve, at least
in part, generation of reactive oxygen intermediates and activation of
p21ras and ERK1/2
kinases.10 14
Recently, a specific AGE, carboxy(methyl lysine) adducts of proteins,
has been shown to bind RAGE and mediate cellular activation, both in
vitro and in vivo.15
Evidence definitively linking RAGE to these ligand-mediated effects was
demonstrated by blockade of AGE-mediated activation of NF-B in the
presence of blocking antibodies to RAGE, soluble RAGE (sRAGE; the
extracellular ligand-binding domain), or transient transfection into
wild-type RAGE-bearing cells of a construct in which solely the
cytosolic domain of the receptor was deleted. In the latter case, a
dominant-negative effect resulted, as AGE-stimulated activation of
NF-B was significantly
suppressed.15 16 |
Activation of NF-B: Role of
Hyperglycemia
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TopIntroductionActivation of NF-{kappa}B: Role...Activation of NF-{kappa}B: Role...Effects of Insulin: A...Is NF-{kappa}B a Logical...References |
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Indeed, hyperglycemia itself has been linked to activation of NF-
B in vascular cells. Work from Nishikawa et
al17 showed that
exposure of cultured bovine aortic endothelial cells to physiologically
relevant concentrations of glucose, 30 mmol/L, resulted in enhanced
nuclear translocation of NF-B. A critical role for generation of
intracellular oxidant stress, largely by mitochondrial oxidants, in
glucose-mediated activation of NF-B was shown. In addition, previous
studies by Yerneni et
al18 indicated that
exposure of VSMCs to hyperglycemia also prompted activation of NF-B.
Consistent with the concept that the vascular milieu in syndromes such
as insulin resistance is quite complex, those investigators found that
exposure of VSMCs to TNF-, platelet-derived growth factor, epidermal
growth factor, or insulin-like growth factor-1 augmented the effects of
hyperglycemia on NF-B activation. Together with other known stimuli
linked to activation of NF-B, such as oxidized lipoproteins and
angiotensin-II, it is reasonable to propose that multiple intertwined
factors associated with syndromes of type 2 diabetes and insulin
resistance may contribute to the process of vascular activation and
atherogenesis. |
Effects of Insulin: A Priming Step in
Activation of NF-B in VSMCs
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TopIntroductionActivation of NF-{kappa}B: Role...Activation of NF-{kappa}B: Role...Effects of Insulin: A...Is NF-{kappa}B a Logical...References |
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In this context, the studies presented by Golovchenko et al5 have sought to test the hypothesis that insulin alone, or in concert with other vascular-perturbing factors, modulates activation of NF-
B in the
vessel wall. In this study, the authors extend their previous
observation that a novel property of insulin is its ability to activate
prenyl transferases, farnesyltransferases, and
geranylgeranyltransferases I and
II.19 20
Because these molecules possess the capacity to posttranslationally
modify Ras, Rho, and Rab proteins, their activation links them to
signal transduction pathways. Golovchenko et
al5 show that
incubation of VSMCs with insulin (largely at physiologically relevant
doses) increased availability of geranylgeranylated Rho-A, thereby
invoking an established mechanism to link increased levels of insulin
to activation of
NF-B.21 It is
important to note that insulin alone did not enhance activation of
NF-B in this system. However, in VSMCs, insulin, and AGEs,
hyperglycemia or angiotensin II synergized to enhance NF-B
activation to even greater degrees than that observed by any of these
mediators alone. These studies suggest that insulin primes the
vasculature for enhanced activation on contact with these traditional
mediators and provide support for the concept that the vascular
microenvironment in type 2 diabetes or syndromes of insulin resistance
is enriched in factors that appear to lead to a common pathway,
activation of NF-B.
However, these findings must be viewed in context,
considering that activation of NF-B is likely not the whole story.
It is certain that other transcription factors linked to cellular
stress response mechanisms act in concert with NF-B to regulate
specific gene expression. Such regulation provides an exquisite degree
of specificity, for example, in individual cell types or during
discrete periods of development. Therefore, future studies in this area
should determine to what degree other key stress response transcription
factors, such as activator
protein-1,22
participate in insulin-mediated effects on vascular
function.
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Is NF-B a Logical Target for Intervention in
Diabetes and Hyperinsulinemia: "Good" and "Bad"
NF-B?
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TopIntroductionActivation of NF-{kappa}B: Role...Activation of NF-{kappa}B: Role...Effects of Insulin: A...Is NF-{kappa}B a Logical...References |
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From these considerations, one might conclude that NF-
B is a logical target to prevent or suppress the
vascular-perturbing properties of a range of injurious molecules linked
to diabetes and insulin resistance, from oxidized lipoproteins, to
AGEs, to high levels of glucose or insulin. Although results of future
studies must be the final arbiter of this issue, it is highly likely
that the "good" side of NF-B will preclude its inhibition, at
least in a global manner. In addition to its likely role in innate
cellular defenses, the classic example of a devastating outcome
secondary to lack of functional NF-B complex was demonstrated by
studies in which the RelA subunit (p65) was genetically deleted in
mice. Embryonic lethality ensued, attributable to massive apoptosis of
liver cells.23 This
critical finding highlighted important antiapoptotic functions (at
least in certain circumstances) of NF-B. Studies in mature animals,
for example, have shown NF-B, and one of its target genes, TNF-,
to be critical for hepatocyte recovery and regeneration after extensive
hepatectomy.24 The
beneficial effects of enhanced activation of NF-B are not limited to
liver development or the response of this organ to extensive resection.
For example, activation of NF-B has been linked to protection
against apoptosis in
VSMCs25 and to
activation of manganese superoxide dismutase in hippocampal neurons
exposed to oxidative
insults.26 These
seeming paradoxes underscore the concept that NF-B subserves innate
functions of host defense and response, at least to certain cellular
stresses.
It is important to note, however, only upon delineation of
the precise molecular participants in the NF-B cascade that mediate
selectively "good" inflammation/resolution and regeneration versus
"bad" inflammation/tissue injury and loss, may blockade of NF-B
be a tenable target for therapeutic intervention
(Figure
).
It is possible, however, that both the exquisite regulation of
activation of
NF-B,27 as well
as the extensive network of crosstalk among the pathways, will reduce
the feasibility of targeting NF-B. In the end, it is likely that
blockade of triggering events at the cell surface will provide the most
logical site to dissect beneficial, innate host responses, from those
that otherwise lead to a smoldering cascade of ongoing cellular
activation and irreparable damage. Furthermore, identification of the
full range of genes turned on by mediators in type 2
diabetes/hyperinsulinemia, such as insulin, AGEs, hyperglycemia, and
oxidized lipoproteins, will shed light on multiple and, possibly,
unique sites for intervention. The emerging use of microarray
technology, indeed, represents a most potent tool in the vascular
biology of diabetes and insulin
resistance.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionActivation of NF-{kappa}B: Role...Activation of NF-{kappa}B: Role...Effects of Insulin: A...Is NF-{kappa}B a Logical...References |
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