Lipid Inflammatory Mediators in Diabetic Vascular Disease

Rama Natarajan and Jerry L. Nadler

Arterioscler Thromb Vasc Biol. 2004;24:1542-1548; originally published online May 27, 2004;
doi: 10.1161/01.ATV.0000133606.69732.4c
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ATVB in Focus
Diabetic Vascular Disease: Pathophysiological Mechanisms in the Diabetic
Milieu and Therapeutic Implications
Series Editor:

Richard A. Cohen

Previous Brief Review in this Series:

Naka Y, Bucciarelli LG, Wendt T, Lee LK, Rong LL, Ramasamy R, Yan SF, Schmidt AM. RAGE axis: animal
models and novel insights into the vascular complications of diabetes. 2004;24:13421349.

Lipid Inflammatory Mediators in Diabetic Vascular Disease

Rama Natarajan, Jerry L. Nadler
AbstractType 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as
atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain
inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular
adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to
play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently,
data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of
atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism.
These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid
metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in
vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes
are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and
cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the
pathogenesis of diabetic vascular disease. (Arterioscler Thromb Vasc Biol. 2004;24:1542-1548.)
Key Words: lipoxygenase diabetes diabetes complications inflammation lipids

iabetes is associated with significantly accelerated rates

of cardiovascular complications such as atherosclerosis
and hypertension. In particular, type 2 diabetes is associated
with 2- to 4-fold increase in coronary artery disease.1 This has
been attributed to the clustering of several risk factors,
including insulin resistance, hypertension, obesity, and dyslipidemia.2,3 Multiple mechanisms contribute to vascular and
arterial disease in the diabetic population.2 Basic biochemical
mechanisms have been described by which hyperglycemiainduced oxidant stress activates several downstream signals
that mediate diabetic complications.4 8 Furthermore, advanced glycation end products formed by glucose-induced
modification of proteins can act via their receptors such as

RAGE and induce cellular oxidant stress, inflammation, and

vascular dysfunction in diabetes.9 12 Recent evidence from
laboratory and clinical studies demonstrates that diabetic
atherosclerosis is not simply a disease of hyperlipidemia but
also an inflammatory disorder involving multiple mediators
such as C-reactive protein, cytokines such as tumor necrosis
factor alpha, and interluekin-6 (IL-6).2,13,14 A recent gene
profiling study showed that high glucose treatment of monocytes leads to increased expression of multiple inflammatory
cytokines, chemokines, and related factors, many of which
are regulated by the proinflammatory transcription factor,
nuclear factor-kappa B (NF-B).15 The recognition now that
highly effective antidiabetic agents, such as thiazolidinedio-

Received February 9, 2004; revision received May 2, 2004; accepted May 12, 2004.
From the Gonda Diabetes Research Center (R.N.), Beckman Research Institute of City of Hope, Duarte Calif; and the Diabetes and Hormone Center
of Excellence (J.L.N.), University of Virginia School of Medicine, Charlottesville, Va.
Correspondence to Dr Rama Natarajan, Gonda Diabetes Research Center, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte,
CA 91010. E-mail RNatarajan@coh.org; or to Dr Jerry L. Nadler, Diabetes & Hormone Center of Excellence, University of Virginia School of Medicine,
450 Ray C Hunt Drive, Fontaine Medical Research Bldg, Charlottesville, VA 22908. E-mail jln2n@virginia.edu
2004 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org

DOI: 10.1161/01.ATV.0000133606.69732.4c

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Natarajan and Nadler

Figure 1. Metabolism of arachidonic acid. The cellular actions of

growth factors, cytokines, and other agonists can lead to the
activation phospholipases and thereby release arachidonic acid.
Arachidonic acid can then be metabolized by the cyclooxygenase, lipoxygenase, and cytochrome P-450 enzymes to various
bioactive molecules. Note that certain LO enzymes, including
12- and 15-LO, can also react with other fatty acid substrates,
such as linoleic acid, to yield additional products.

nes, and lipid-lowering agents, such as statins, possess

antiinflammatory properties underscores the major role
played by inflammatory mediators in the cardiovascular
complications of diabetes. However, although the actions of
inflammatory peptide growth factors, cytokines, and acute
phase reactants have been fairly well studied, much less is
known about the actions of the oxidized lipids and eicosanoids generated by these factors during cellular activation.
These oxidized lipids, generated by the action of the lipoxygenase and cyclooxygenase enzymes, are produced under
diabetic conditions and have potent proatherogenic effects in
vessel wall cells. This review highlights the role of these
pathways and their lipid products in the pathogenesis of
diabetic vascular disease.

The Cyclooxygenase and Lipoxygenase Pathways

When growth factors and cytokines bind to their cell surface
receptors, they can activate several phospholipases, which act
on membrane phospholipids to release arachidonic acid, a
precursor for several eicosanoids with potent biological
effects.16,17 Arachidonic acid can be metabolized by 3 major
oxidative pathways: the cyclooxygenase (COX) pathway that
forms prostaglandins; the lipoxygenase (LO) pathway, which
forms hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and thirdly, the cytochrome P-450 monooxygenase
pathway that forms epoxides and HETEs18 (Figure 1). Products of the cytochrome P450 metabolic pathway have potent
vasoactive properties, particularly in the kidney,19 but there
are no reports of their involvement in diabetic vascular
disease. COX-1 and COX-2 enzymes catalyze the first step in
the biosynthesis of prostaglandins (PGs) by converting arachidonic acid to PGH2.20 24 PGH2 is further converted into
other PGs and eicosanoids such as PGE2, PGD2, PGF2, PGI2
(prostacyclin), and thromboxane18,20 (Figure 1). COX-1 is
constitutively expressed in most cells and plays a role in basal
physiological functions in several cells and tissues. COX-2,
however, is usually expressed at low or undetectable levels in

Diabetes, Inflammation, and Vascular Disease

1543

most tissues and cells but is significantly induced by stimuli

such as lipopolysaccharide, cytokines such as interleukin
(IL)-1, IL-1, and tumor necrosis factor-, and by growth
factors.20 24 An exception is seen in some tissues,24 including
the pancreatic islet that constitutively and dominantly expresses COX-2,25,26 and where its products such as PGE2 are
believed to play a role in inflammation, islet destruction, and
inhibition of insulin secretion associated with type 1 diabetes.2528 COX-2 and its products also have renal functions and
vascular effects.29,30 They are implicated in the pathogenesis
of several inflammatory diseases, and selective inhibition of
COX-2 is effective in reversing inflammation without gastric
side effects.20,21,24,30 Although COX-2 can form the vasodilatory and protective prostacyclin, it also produces the potent
inflammatory prostaglandin, PGE2.2124
The lipoxygenase (LOs) are mainly classified as 5-, 8-, 12or 15-LO, based on their ability to insert molecular oxygen at
the corresponding carbon position of arachidonic acid (Figure
1).3133 The 5-LO pathway leads to the formation of 5(S)HETE and leukotrienes. Proinflammatory leukotrienes have
been implicated in the pathogenesis of atherosclerosis, but
very little is known regarding their role in diabetes. The 12and 15-LOs can form 12(S)- and 15(S)-HETEs from arachidonic acid. The production of 12(S)- and 15(S)-HETE has
been shown in several vascular tissues and cells, including
cultured vascular smooth muscle cells (VSMC), endothelial
cells, and monocytes. LO products may play important roles
in the pathogenesis of hypertension, atherosclerosis, and
diabetes, as discussed more in detail later in the review.
Functionally distinct isoforms of 12-LO have been cloned,
including platelet, leukocyte, and epidermal 12-LOs.3137
Human and rabbit 15-LOs and the leukocyte 12-LO have
high homology and are classified as 12/15-LOs because they
can form both 12(S)-HETE and 15(S)-HETE from arachidonic acid via their hydroperoxy precursors and mainly hydroperoxyocatadecadienoic acids [13(S)-and 9(S)-HPODE]
and hydroxyocatadecadienoic acids from linoleic acid.31,38
The 12/15-LO has been detected in porcine leukocytes,34
VSMC,39 endothelial cells,40 42 and in several rat and mouse
tissues.43 45

The Cyclooxygenase Pathway in Diabetic

Vascular Disease
COX-2 and its proinflammatory products have been implicated in the pathogenesis of several inflammatory diseases
including atherosclerosis because COX-2 products such as
PGE2 and thromboxane have potent proinflammatory and
vasoconstrictor properties.20 24,46 Furthermore, augmented
expression of COX-2 was noted in atherosclerotic lesions,47
and COX-2 could promote lesion formation in low-density
lipoprotein (LDL) receptor-deficient mice.48 Because COX-2
inhibitors also block formation of the protective prostacyclin
(PGI2), studies have been performed to determine whether
these inhibitors could worsen atherosclerosis.30 Earlier studies showed that elevated glucose can stimulate the generation
of endothelium-derived vasoconstrictor prostanoids such as
thromboxane-A2.49 However, the potential involvement of
COX-2 in diabetic vascular complications, diabetic atherosclerosis, or the regulation of COX-2 in relevant cells under

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Arterioscler Thromb Vasc Biol.

September 2004

diabetic conditions is only now becoming evident. In endothelial cells, high-glucose (HG) treatment increased COX-2
expression and decreased nitric oxide availability.50 Very
recently, COX-2 activity and expression were shown to be
upregulated by high glucose as well as ligands of the receptor
for advanced glycation end products (RAGE) in monocytes,
and this appeared to be primarily mediated by NF-B
activation.51,52 Increased oxidant stress and protein kinase C
activation under diabetic conditions could be contributory
factors. Interestingly, COX-2 expression was also markedly
increased in monocytes from diabetic patients.51,52 Furthermore, new data show that diabetic conditions can lead to
chromatin remodeling and histone acetylation at the COX-2
gene promoter at NF-B binding sites.53 COX-2 also seemed
to mediate monocyte adhesive interactions.51 A recent report
demonstrated that in humans, RAGE overexpression is associated with enhanced inflammatory reactions and COX-2
expression in diabetic plaque macrophages, and that this
effect could also contribute to plaque destabilization by
inducing metalloproteinase expression.54 There was a significant correlation between plasma levels of hemoglobin A1c
and RAGE and COX-2 expression. These results suggest that
apart from its documented role in pancreatic islet dysfunction,
COX-2 may be a key inflammatory mediator in the pathogenesis of diabetic atherosclerosis. Thus, the diabetic state
can increase COX-2 expression and activity in vascular cells
and monocytes and thereby aggravate downstream inflammatory and vascular events. It is also possible that 12/15-LO
activation can increase COX-2 transcription based on studies
in pancreatic islet beta cells.55

The Lipoxygenase Pathway in Atherosclerosis,

Restenosis, Diabetes, and Insulin Resistance
LO enzymes and their products, namely HETEs and hydroxyocatadecadienoic acids, have been implicated in the
pathogenesis of atherosclerosis. The 12/15-LO enzyme can
mediate the oxidative modification of low-density lipoprotein
(LDL) to the atherogenic oxidized LDL.56,57 Furthermore,
angiotensin II (AII) could increase macrophage-mediated
modification of LDL via the 12/15-LO pathway.58 Animal
models have demonstrated the key role of the LO pathway in
the pathogenesis of atherosclerosis and restenosis. Overexpression of 15-LO in the vascular endothelium could accelerate atherosclerosis in LDL receptor-deficient mice.59
Leukocyte-type 12/15-LO mRNA and protein were observed
in porcine atherosclerotic lesions, which were greatly augmented in diabetic and hyperlipemic pigs displaying accelerated atherosclerosis.60 LO activation may also play a role in
neointimal thickening associated with restenosis because
there was a marked increase in 12/15-LO expression in
balloon-injured rat carotid arteries relative to uninjured.
Furthermore, pretreatment with a ribozyme targeted to rat
12/15-LO could significantly reduce neointimal thickening in
this rat model.61 Convincing evidence supporting a pathological role for leukocyte 12/15-LO in atherosclerosis comes
from recent reports showing marked decrease in atherosclerosis in apo E/ mice and LDLR/ that were cross-bred with
leukocyte 12/15-LO/ mice.62,63 Furthermore, a novel inflammatory link was suggested because the macrophages

from 12/15-LO/ mice had a selective defect in lipopolysaccharide-induced IL-12 synthesis.64 An interesting genetic
study suggests that 5-LO may be an important proatherogenic
gene locus.65 Also, 5-LO was abundantly expressed in atherosclerotic lesions,66 and it has been suggested that 5-LO
may mediate specific stages of atherosclerosis.67 However,
the role of 5-LO in diabetic vascular disease is not yet known.
Overall, available evidence suggests that the LOs can contribute to the pathology of atherosclerosis and diabetic vascular disease by virtue of their capacity to oxidize LDL, to
induce growth and inflammatory events, and by being in an
atherogenic gene locus. The relative importance of the
different LOs in this regard is not yet clear. Because the
12/15-LO pathway can be upregulated by hyperglycemia,
growth factors, and cytokines, it is likely that it can augment
diabetic atherosclerosis and vice versa, thereby setting off a
vicious loop of events.
HG culture enhanced 12/15-LO pathway activation and
expression in VSMC39 and endothelial cells.42 Furthermore,
AII-induced 12/15-LO activity in VSMC was greater in HG
relative to normal glucose.39 Apart from AII, 12/15-LO
activity and expression in VSMC could also be potently
upregulated by platelet-derived growth factor (PDGF) BB
and by cytokines such as IL-1, IL-4, and IL-8 in VSMC.68,69
The 15-LO expression was induced in monocytes and endothelial cells by IL-4 or IL-13.41,70 72 Thus, 12/15-LO in
vascular and mononuclear cells can be induced by diabetic
conditions, growth factors, and cytokines, and may contribute
to their biological and atherogenic effects.
The LO pathway may therefore play a role in the cardiovascular complications associated with diabetes. Endothelial
cells and VSMC cultured under hyperglycemic conditions
produced increased amounts of HETEs.39,42,73 Furthermore,
HG-induced adhesion of monocytes to endothelial cells could
be mediated by the LO pathway.42,74 The 12/15-LO products
also appear to mediate minimally modified LDL-induced
monocyte binding to endothelial cells.75 LO products have
potent chemotactic and hypertrophic effects in VSMC.76 78
The hypertrophic effects of 12(S)-HETE in VSMC were
markedly enhanced under HG culture conditions in a manner
similar to those of angiotensin II.77 There is now considerable
evidence to support a role for 12/15-LO in promoting the
development of diabetes and atherosclerosis. Bleich et al
noted that 12/15-LO deficient mice were resistant to the
development of diabetes.79 In vivo relevance of 12/15-LO in
human diabetes was suggested by a study demonstrating
increased urinary excretion of 12(S)-HETE in diabetic subjects compared with matched nondiabetic controls.80 Interestingly, these diabetic subjects also had decreased urinary
prostacyclin levels, suggesting a potential shunting into the
12/15-LO pathway. Recently, increased 12/15-LO expression
was noted in a swine model of hyperlipidemia and diabetesinduced accelerated atherosclerosis.60 Diabetes and hyperlipidemia alone increased both monocyte oxidant stress and
12/15-LO expression in arteries, but the combination of these
2 risk factors in this swine model led to not only a marked
acceleration of atherosclerosis but also a synergistic increase
in oxidant stress and 12/15-LO activation.60 A recent report
demonstrated increased expression of 12/15-LO in urine and

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Natarajan and Nadler

endothelial cells from diabetic db/db mice.81 Interestingly, it
was noted that the increased production of 12/15-LO products
by the endothelial cells of the db/db mice was responsible for
the observed increased in binding of monocytes to the
endothelial cells from db/db versus those from control mice,
and it was concluded that the 12/15-LO pathway is important
for mediating early vascular changes and inflammatory reactions in diabetes.81 Taken together, these results suggest an in
vivo role for leukocyte type 12/15-LO in diabetic
atherosclerosis.
Emerging evidence supports a clear role of insulin resistance and diabetes in leading to accelerated cardiovascular
disease. As discussed, elevated glucose and diabetes increase
the expression and activity of 12/15-LO. However, fewer
reports have evaluated the role of 12/15-LO in metabolic
disturbances seen in the insulin resistance syndrome. Of
interest are studies showing that masoprocol, a LO inhibitor,
can reduce triglycerides, free fatty acids, and improve insulin
action in both fructose-fed and fat-fed rat models of insulin
resistance and type 2 diabetes.82,83 In addition, 12-LO products can downregulate glucose transport in VSMC.84 To
further evaluate the effect of insulin resistance on vascular
injury responses and 12/15-LO expression, we studied the
effect of carotid balloon injury in lean and obese insulin-resistant Zucker rats. After injury, the intima-to-media ratio of
obese Zucker rats was significantly greater than leans starting
at 14 days after injury and persisting up to at least day 30. The
expression of inflammatory mediators including 12/15-LO
and IL-6 were markedly increased in obese compared with
lean animals suggesting that vascular injury in obese Zucker
rats is associated with inflammation. Increased macrophage
and p-selectin staining was also seen. These studies (unpublished) indicate an exaggerated injury response in the insulin
resistant obese Zucker rat model and that inflammation may
play a major role in mediating neointimal growth under these
conditions. In addition, 12/15-LO was one of the few genes
upregulated in the pancreatic beta cell of the insulin resistant
prediabetic Zucker diabetic fatty rat,85 thereby suggesting that
12/15-LO expression is enhanced in the prediabetic metabolic
syndrome condition before frank hyperglycemia. Thus 12/
15-LO may have a role in the excess cardiovascular disease
seen even before diabetes is diagnosed. Because hyperglycemia alone also increases 12/15-LO expression in vascular
cells, it is likely that 12/15-LO can participate in the development of type 2 diabetes and atherosclerosis, whereas the
associated hyperglycemia, dyslipidemia, and insulin resistance can further augment 12/15-LO pathway activation to set
off a vicious loop of inflammatory events. Furthermore,
factors such as growth factors, cytokines, and advanced
glycation end products, all of which are relevant to the
pathogenesis of diabetes, can also upregulate the activity and
expression of 12/15-LO (Figure 2).

Lipoxygenase Products Have Growth,

Chemotactic, Adhesive, and Inflammatory Effects
in VSMC and Endothelial Cells
Treatment of human aortic endothelial cells with 12(S)HETE, but not 12(R)-HETE, increased monocyte binding to
the endothelial cells, a key early step in the development of

Diabetes, Inflammation, and Vascular Disease

1545

Figure 2. Actions of 12/15-LO in the vessel wall. Induction of

12/15-LO and its products in endothelial cells by factors such
as HG and AGEs can lead to oxidant stress, release of chemokines, activation of monocyte integrins, and key endothelial
adhesive molecules and thereby lead to endothelial dysfunction,
monocyte activation, and adhesion. In VSMC, similarly,
12/15-LO and its products can induce oxidant stress, adhesion
molecules, extracellular matrix proteins, release of inflammatory
cytokines, and chemokines, thereby leading to VSMC hypertrophy, migration, and inflammatory responses. 12/15-LO in monocyte/macrophages, endothelial cells, and VSMC can mediate
LDL oxidation to oxidized LDL.

atherosclerosis.74 Furthermore, the 12/15-LO ribozyme

blocked high-glucoseinduced binding of monocytes to endothelial cells, suggesting that glucose-induced LO activation
in endothelial cells may lead to endothelial activation and
dysfunction.42 The 12(S)-HETE increased the expression of
CS-1 fibronectin on endothelial cells, which could be a key
mechanism for inducing monocyte adhesion. Certain LO
products also increased the surface expression of key inflammatory adhesion molecules such as VCAM-1 via activation
of the transcription factor, NF-B.86,87 LO products also
directly increased migration, cellular hypertrophy, and fibronectin synthesis in VSMC.76 78 Angiotensin II (AII)induced increases in total cellular protein content of porcine
VSMC were significantly attenuated by a specific LO inhibitor.77 Furthermore, direct addition of the 12-LO product,
12(S)-HETE, increased total cell protein content and fibronectin levels to nearly the same extent as AII.77,78 A rat
12/15-LO ribozyme could significantly inhibit HG-induced
fibronectin production.61 Because AII and HG culture can
increase the formation of LO products, it is attractive to
speculate that the enhanced growth-promoting and matrix
effects of the LO products formed by AII and HG are
potential mechanisms for the accelerated growth of VSMC
and enhanced hypertrophic effects of AII under HG conditions. In support of this, it was noted that rat VSMC and

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Arterioscler Thromb Vasc Biol.

September 2004

cardiac fibroblasts stably expressing mouse 12/15-LO

showed increased growth properties.78,88 In addition, pharmacological LO inhibitors, as well as the 12/15-LO ribozyme,
could also significantly inhibit PDGF-induced migration of
VSMC.42,68 Because PDGF can upregulate 12/15-LO,68 LO
activation may mediate, at least in part, the chemotactic
effects of PDGF.
LO products also have proinflammatory effects in VSMC.
Thus the 12/15-LO product of linoleic acid, 13-HPODE, led
to a significant increase in the activation of the redoxsensitive and inflammatory transcription factor, NF-B in
VSMC.87 This was associated with increased transcription of
the inflammatory adhesion molecule VCAM-1 and the potent
chemokines monocyte chemoattractant protein-1 via an NFB dependent mechanism.87,89

Signal Transduction and Gene Regulation

Mechanisms by Which LO Products Mediate
Their Cellular Actions
HETEs can activate certain isoforms of protein kinase C
directly or indirectly by incorporating into membrane phospholipids, which then generate HETE-containing diacylglycerol species to activate protein kinase C.90 They can also
activate several mitogen activated protein kinases (MAPKs)
and thereby activate key transcription factors that mediate the
expression of growth and inflammatory genes.78,90 In VSMC,
12(S)-HETE could lead to the transcription of the fibronectin
gene, and this was regulated by the transcription factor CREB
in a p38MAPK-dependent manner.78 However, the hydroperoxy LO product, 13(S)-HPODE, could increase the expression of VCAM-1 in an NF-B dependent manner and partly
via p38MAPK.87 Thus these oxidized lipids can serve as
novel signal transducers, regulators, and amplifiers of gene
induction by high glucose, growth factor, and cytokine
actions. Interestingly, a novel role for HPODE and hydroperoxy precursor as seeding molecules responsible for LDL
oxidation by artery wall cells and associated oxidative events
related to the pathogenesis of atherosclerosis has been demonstrated.91 In monocytes, 9-hydroxyocatadecadienoic acid
and 13-hydroxyocatadecadienoic acid (12/15-LO products of
linoleic acid metabolism) induced the expression of the
scavenger receptor, CD36, apparently via activation of the
nuclear receptor, peroxisome proliferator activator-gamma.92
IL-4 induced 12/15-LO activation was also implicated in this
process.93
Coffey et al demonstrated that 12/15-LO can lead to the
catalytic consumption of the vasodilator, nitric oxide, and
prevent nitric oxide-mediated soluble guanylate cyclase activation.94 This suggests that 12/15-LO may mediate the
pathology of vascular diseases such as atherosclerosis, hypertension, and diabetes not only by the bioactivity of their lipid
products but also by limiting the availability of nitric oxide in
the vessel wall. Reactive oxygen species generated during LO
pathway activation95 may mediate growth and inflammatory
effects in VSMC and endothelial cells. Conversely, highglucose induced oxidant stress, and reactive oxygen species
in diabetes can lead to the induction of 12/15-LO in VSMC
and endothelial cells and promote cellular dysfunction. Recent reports show that VSMC derived from 12/15-LO/ mice

grow slower than those derived from genetic control mice,

produce much lesser amounts of superoxide, and have reduced activation of MAPKs,96 whereas endothelial cells
derived from these 12/15-LO KO mice display decreased
binding to monocytes compared with those from control
mice.97 However, new data show that endothelial cells from
12/15-LO transgenic mice reciprocally display enhanced
monocyte binding relative to those from control mice.97
Interestingly, these 12/15-LO transgenic mice also developed
more atherosclerotic lesions.97 Overall, it appears that 12/
15-LO can participate in an inflammatory loop with cytokines
and other inflammatory genes to amplify or modulate their
cellular responses and thereby accelerate the development of
cardiovascular complications in diabetes.
In summary, LO and COX-2 enzymes in vascular, inflammatory, and other cells can form products with pleiotropic
physiological and pathological effects. These include vasoactive, growth, adhesive, chemotactic, oxidative, and inflammatory responses, which therefore implicate them in the
pathogenesis of diabetic vascular disease such as atherosclerosis and hypertension. Although COX-2specific inhibitors
are now available for clinical use, there are currently no
clinically safe, pharmacologically selective, and optimally
bioavailable inhibitors of 12/15-LO. Hence, the development
of 12/15-LO inhibitors, including novel ribozymes, may lead
to new antiinflammatory therapies for diabetic vascular
complications.

Acknowledgments
We acknowledge grant support from the National Institutes of Health
(PO1 HL55798, RO1 DK55240, RO1 DK065073, and RO1
DK58191) and the Juvenile Diabetes Research Foundation International. We thank Dr Q. Cai for his help with the manuscript.

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