© 2001 American Heart Association, Inc.
Editorial |
Antiatherogenic Effects of Thiazolidinediones?
From the Department of Medicine, University of California at San Diego, La Jolla.
Correspondence to Dr Christopher Glass, Department of Medicine, Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0651.
Treatment of type 2 diabetes mellitus (DM) is directed at relieving symptoms of hyperglycemia and reducing the incidence of diabetes-associated pathologies. Complications of atherosclerosis, including myocardial infarction and stroke, are the most common causes of death in diabetic patients. Thiazolidinediones (TZDs) represent a relatively recent addition to the arsenal of pharmaceutical options for diabetes treatment. These agents are potent insulin sensitizers and significantly improve glycemic control in the majority of diabetic patients.1 Troglitazone, the first TZD to be marketed, has been replaced in clinical practice by the more potent TZDs, rosiglitazone and pioglitazone. There are now upwards of a million diabetic patients taking these agents in the United States, and the rising incidence of obesity and type 2 DM predicts an ever-growing patient population of patients who will be candidates for treatment with insulin sensitizers.
Given their antidiabetic actions, TZDs would be
expected to reduce atherosclerotic complications. Although there are a
few hints from small clinical studies that this may be the case, TZDs
have not been in clinical use for sufficient time to establish their
long-term effects on the development and clinical consequences of
atherosclerosis in diabetic patients. In 1995,
troglitazone was found to be a high-affinity ligand for the peroxisome
proliferator–activated receptor-
(PPAR-).2 There is now
extensive evidence that the TZD class of molecules exerts its
insulin-sensitizing effects through this
receptor.3 PPAR- is a
ligand-activated transcription factor that is related to
receptors for steroid and thyroid hormones. In addition to regulating
glucose homeostasis, it has been shown to play important roles in the
development of adipose
tissue.4 PPAR- exerts its
biological effects by activating or repressing gene transcription,
although the specific target genes that are responsible for the
insulin-sensitizing effects of TZDs remain to be
established.
A potential connection of PPARs to the development of atherosclerosis was first suggested by studies demonstrating that TZDs could inhibit vascular smooth muscle cell growth and intimal hyperplasia in a balloon injury model in rats.5 Smooth muscle cell migration and proliferation are important during the progression of atherosclerosis from early to intermediate lesions. However, the initiation of atherosclerosis is believed to involve the adhesion of monocytes to activated endothelial cells at lesion-prone sites in the artery wall.6 These cells subsequently migrate into the subendothelial space in response to chemotactic signals, such as macrophage chemotactic protein-1 (MCP-1), and differentiate into macrophages. This program of differentiation includes the upregulation of scavenger receptors, including CD36 and scavenger receptor-A, that are capable of mediating the uptake of oxidized forms of LDL (oxLDL). In the presence of sufficient oxLDL, this pathway leads to formation of macrophage foam cells that are the major cellular elements of fatty streaks, the earliest recognizable atherosclerotic lesions.
Evidence that PPAR- might influence
macrophage-dependent events in the development of
atherosclerosis was initially suggested by a series of
articles that appeared in 1998. PPAR- was demonstrated to be
expressed not only in normal human monocytes and murine
macrophages but also in macrophage foam cells of human
and murine atherosclerotic
lesions.7 8 9 10
Natural and synthetic PPAR- ligands were demonstrated to inhibit
expression of inflammatory response genes in cultured
macrophages, suggesting that PPAR- might play a
physiological role as a negative regulator of
macrophage
activation.7 11
Because atherosclerosis can be considered to be a form
of chronic inflammation, these observations also raised the possibility
that TZDs might exert antiatherogenic effects within the vessel wall.
An opposing view emerged from the discovery that the CD36 gene is a
direct target of PPAR- and that oxidized lipids present in oxLDL
can serve as activating ligands of
PPAR-.9 10
These observations formed the basis of a hypothetical "PPAR-
cycle," in which stimulation of PPAR- would lead to upregulation
of CD36, mediating increased uptake of ox LDL. OxLDL lipids brought
into the cell via CD36 would complete the cycle by further stimulation
of PPAR- activity and CD36 expression. Such a cycle was predicted to
promote foam cell formation and the development of
atherosclerosis.9
Recent studies in which apolipoprotein E–deficient mice were crossed
with CD36-deficient mice demonstrated that mice lacking CD36 developed
significantly less atherosclerosis, consistent
with this
possibility.12
The article by Law and
colleagues13 in this issue
of Arteriosclerosis,
Thrombosis, and Vascular
Biology and a recent article
from our laboratory14
provide the first assessment of the effects of TZDs on the development
of atherosclerosis in
hypercholesterolemic animal models. In concert, these
studies confirm both proatherogenic and antiatherogenic activities of
PPAR- in the vessel wall and demonstrate that antiatherogenic
effects prevail in male mice. The study by Law and colleagues examined
the effects of troglitazone on the development of
atherosclerosis in male LDL receptor gene–deleted
(LDLR-/-) mice under 2 dietary conditions.
In 1 condition, animals were fed a high-fat,
high-cholesterol diet that led to marked
hypercholesterolemia and mild insulin
resistance. In the second dietary condition, mice were fed a
high-cholesterol, high-fructose diet that led to marked
hypercholesterolemia but did not induce insulin
resistance. Troglitazone inhibited the development of
atherosclerosis by 30% in the high-fat group and by
42% in the high-fructose group. Although metabolic effects
cannot be excluded, morphometric analysis of the
macrophage content of lesions suggested that antiatherogenic
effects of troglitazone were related, in part, to decreased monocyte
recruitment. Consistent with this, in vitro studies
demonstrated that troglitazone inhibited
transendothelial migration of THP-1 monocytes in
response to MCP-1. This effect may reflect the recent observation that
TZDs can downregulate expression of chemokine receptor 2 (CCR2),
the receptor for MCP-1, in murine and human monocytes. A potential
caveat to the studies of Law and colleagues is that troglitazone
contains a vitamin E moiety and could in theory inhibit the development
of atherosclerosis by preventing oxidation of LDL
directly. This is unlikely, however, as the equivalent dose of vitamin
E received by these animals is much lower than that reported to affect
atherosclerosis.
The recent article by Li et
al13 examined the effects of
rosiglitazone and the tyrosine-based PPAR- ligand GW7845 on the
development of atherosclerosis in male and female
LDLR-/- mice. These mice were fed a
high-fat, high-cholesterol diet that induced marked
hypercholesterolemia and mild insulin
resistance, similar to the high-fat, high-cholesterol
treatment group studied by Law et al. Treatment of these mice with
rosiglitazone or GW7845 markedly reduced the extent of
atherosclerosis in male mice. Intriguingly, these drugs
had no significant effect on the development of
atherosclerosis in female mice. Metabolic
studies demonstrated that rosiglitazone and GW7845 improved insulin
resistance in male mice but not in female mice. This lack of an effect
is likely to reflect a species-specific difference between humans and
mice, as TZDs exert insulin-sensitizing effects in women. Rosiglitazone
and GW7845 also reduced HDL cholesterol levels and
increased IDL and VLDL cholesterol in female mice, which
may have prevented protective effects of these agents on the vessel
wall. Studies of gene expression in the artery wall also indicated that
rosiglitazone and GW7845 induced expression of CD36 and decreased
expression of gelatinase-B and tumor necrosis factor-
.
In concert, these 2 studies demonstrate that PPAR-
agonists have the potential to exert potent antiatherogenic effects in
animal models. It is also clear, however, that these agents exert
complex effects on metabolism and the biology of the artery
wall. In the case of male mice, the net effect was a significant
reduction in atherosclerosis, but this was not the case
in the female mice studied by Li et
al.14 It thus cannot yet be
ruled out that in some genetic or environmental backgrounds, TZDs could
actually exacerbate atherosclerosis. It will therefore
be of importance to evaluate the influence of rosiglitazone and
pioglitazone on the development of atherosclerosis in
human patients who are currently taking these drugs. These observations
also suggest that opportunities exist for the development of new
classes of PPAR- ligands that are selected for both
insulin-sensitizing and antiatherogenic activities. There is good
reason to think that this may be possible, based on the development of
selective estrogen receptor modulators that exert proestrogenic effects
on some genes and antiestrogenic effects on
others.15 16
PPAR- ligands with potent antiatherogenic activities might
ultimately be considered for use not only in patients with type 2 DM
but also in nondiabetic patients who are at high risk for development
of atherosclerosis due to other constellations of risk
factors.
References
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