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Am J Physiol Heart Circ Physiol 288: H1037–H1043, 2005;
doi:10.1152/ajpheart.00677.2004.
8TH INTERNATIONAL SYMPOSIUM ON RESISTANCE ARTERIES
New Developments in Resistance Artery Research:
From Molecular Biology to Bedside
Peroxisome proliferator-activated receptors and cardiovascular remodeling
Ernesto L. Schiffrin
Canadian Institute of Health Research Multidisciplinary Research Group on
Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
Submitted 27 July 2004; accepted in final form 28 September 2004
arteries; endothelium; heart; inflammation
evidence suggests that PPAR-␤/␦ is involved in fatty acid and
lipid metabolism, particularly in skeletal muscle (9, 40, 60).
This may also occur in cardiovascular tissues (23). PPAR-␥
controls adipocyte differentiation and lipid storage (60) and is
accordingly highly expressed in adipose tissue. Through its
effects on adipose tissue and skeletal muscle, PPAR-␥ regulates the action of insulin. Selective activators of PPAR-␥ are
the insulin sensitizers thiazolidinediones or glitazones, such as
troglitazone, pioglitazone, and rosiglitazone.
PPARs have an NH2-terminal domain that regulates PPAR
activity, a DNA binding domain that binds to the PPAR
response element (PPRE) in the promoter region of target
genes, a domain for a cofactor, and a COOH-terminal ligandbinding domain that determines ligand specificity (62). PPARs
are bound to corepressor proteins when inactive. After stimulation by PPAR activators, PPARs dissociate from corepressors and recruit coactivators, which include a PPAR-binding
protein and the steroid receptor coactivator-1 (37), and heterodimerize with retinoid X receptor-␣. They then bind to
PPRE in target genes to modulate gene transcription (27). Gene
regulation by this mechanism results in the action of PPARs on
carbohydrate and lipid metabolism (Fig. 1). PPAR-␣ and
PPAR-␥ also exert numerous effects by interaction with different transcription factors to repress proinflammatory genes
(Fig. 1). Although the effects on carbohydrate and lipid metabolism affect the cardiovascular system mainly through their
impact on atherogenesis, the anti-inflammatory and antioxidant
actions of PPARs affect cardiovascular remodeling in many
ways. Effects of PPARs on cardiovascular remodeling are the
main subject of the present review, beyond their regulatory
effects on glucose and lipid metabolism, which have been
reviewed recently (40).
PEROXISOME PROLIFERATOR-ACTIVATED receptors (PPARs) are nuclear factors initially shown to respond to xenobiotics with
peroxisomal proliferation in the rodent liver (30). Later, they
were demonstrated to modulate genes that regulate lipid and
glucose metabolism (for review see Ref. 40). More recently,
PPARs have been shown to participate in the regulation of cell
growth and migration (36), oxidant stress (16, 59), and inflammation (13) in the cardiovascular system. PPAR-␣ is found in
tissues where fatty acid catabolism is important (liver, kidney,
heart, and muscle) and is stimulated by natural ligands such as
fatty acids and eicosanoids (e.g., leukotriene B4) and by synthetic ligands, the lipid-lowering fibrates (14). PPAR-␣ affects
target genes that participate in ␻- and ␤-oxidation of fatty
acids. PPAR-␤/␦ is expressed in many tissues (6, 34). Recent
PPAR-␣ and PPAR-␥ are expressed in the cardiovascular
system (5). PPAR-␣ is found in endothelial cells (28), vascular
smooth muscle cells (VSMCs) (56), and monocytes/macrophages (10). The role of these nuclear factors in the vasculature
and the heart has been revealed over the past few years (40).
The PPAR-␣ ligand docosahexaenoic acid (DHA) was shown
to have proapoptotic effects on cultured VSMCs (19) that were
Address for reprint requests and other correspondence: E. L. Schiffrin,
Clinical Research Institute of Montreal, 110 Pine Ave. W, Montreal, Quebec,
Canada H2W 1R7 (E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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VASCULAR EFFECTS OF PPAR-␣
0363-6135/05 $8.00 Copyright © 2005 the American Physiological Society
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Schiffrin, Ernesto L. Peroxisome proliferator-activated receptors
and cardiovascular remodeling. Am J Physiol Heart Circ Physiol 288:
H1037–H1043, 2005; doi:10.1152/ajpheart.00677.2004.—Peroxisome
proliferator-activated receptors (PPARs) are nuclear receptors that
heterodimerize with the retinoid X receptor and then modulate the
function of many target genes. Three PPARs are known: ␣, ␤/␦, and
␥. The better known are PPAR-␣ and PPAR-␥, which may be
activated by different synthetic agonists, although the endogenous
ligands are unknown. PPAR-␣ is involved in fatty acid oxidation and
expressed in the liver, kidney, and skeletal muscle, whereas PPAR-␥
is involved in fat cell differentiation, lipid storage, and insulin sensitivity. However, both have been shown to be present in variable
amounts in cardiovascular tissues, including endothelium, smooth
muscle cells, macrophages, and the heart. The activators of PPAR-␣
(fibrates) and PPAR-␥ (thiazolidinediones or glitazones) antagonized
the actions of angiotensin II in vivo and in vitro and exerted cardiovascular antioxidant and anti-inflammatory effects. PPAR activators
lowered blood pressure, induced favorable effects on the heart, and
corrected vascular structure and endothelial dysfunction in several
rodent models of hypertension. Activators of PPARs may become
therapeutic agents useful in the prevention of cardiovascular disease
beyond their effects on carbohydrate and lipid metabolism. Some side
effects, such as weight gain, as well as documented aggravation of
advanced heart failure through fluid retention by glitazones, may,
however, limit their therapeutic application in prevention of cardiovascular disease.
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CARDIAC AND VASCULAR EFFECTS OF PPARS
mediated by activation of p38 mitogen-activated protein kinase
(21). Anti-inflammatory effects were demonstrated by the
inhibition by PPAR-␣ ligands of interleukin (IL)-1␤-induced
production of IL-6 and prostaglandins and expression of cyclooxygenase-2. These effects occurred as a consequence of
PPAR-␣ inhibition of signaling by the proinflammatory mediator nuclear factor-␬B (NF-␬B) and induction of apoptosis
(10). Antagonism of signaling by NF-␬B was also demonstrated by other investigators (12, 46). PPAR-␣ activators also
downregulated cytokine-induced genes, such as vascular cell
adhesion molecule (VCAM)-1 and tissue factor, in endothelial
cells (42). PPAR-␣-deficient mice demonstrated enhanced inflammatory responses to lipopolysaccharide (LPS) administration, and, in these mice, fibrates were unable to affect LPSinduced IL-6 (12). The PPAR-␣ activator fenofibrate also
reduced plasma concentrations of the cytokines interferon-␥
and tumor necrosis factor-␣ (TNF-␣) in patients with hyperlipoproteinemia IIb (38).
Because PPARs might antagonize the effects of angiotensin
II (ANG II), the action of the PPAR-␣ activator DHA was
investigated in ANG II-infused rats (16). DHA reduced ANG
II-induced oxidative stress (as demonstrated by NADPH oxidase activity measured by chemiluminescence) and expression
of inflammatory mediators [the adhesion molecules intercellular adhesion molecule (ICAM-1) and VCAM-1] in blood
vessels of ANG II-infused rats. Blood pressure (BP), elevated
by ANG II, was reduced by DHA. The remodeling of small
resistance arteries induced by ANG II was abrogated by the
PPAR-␣ activator. Concomitantly, endothelial dysfunction
typically found under ANG II infusion was prevented by DHA,
together with reduction in NADPH oxidase-dependent superoxide anion formation. Although these effects cannot be conclusively and unambiguously shown to be unrelated to BP
reduction, in some models such as the deoxycorticosterone
acetate (DOCA)-salt hypertensive rat, they have occurred in
response to PPAR-␣ activators in the absence of significant
decline in BP (26). This suggests that they are probably not
dependent on reduction of BP.
Recent studies have elucidated some of the mechanisms
involved in the beneficial effects of PPAR-␣ activation on
endothelial function. Goya et al. (24) demonstrated that fenofibrate increases endothelial nitric oxide (NO) synthase (eNOS)
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expression in bovine aortic endothelial cells. Interestingly, this
does not occur through effects on eNOS gene promoter activity
but, rather, through increases in mRNA stability (24).
VASCULAR EFFECTS OF PPAR-␥
Similar to PPAR-␣, PPAR-␥ has been reported to be present
in the vasculature (40) and was demonstrated in endothelial
cells (52), VSMCs (20, 35), and monocytes/macrophages (50).
PPAR-␥ activators inhibited proliferation and migration of
VSMCs (35, 36). They enhanced expression of PPAR-␥ in
macrophages and inhibited expression of inducible NO synthase (iNOS), matrix metalloproteinase (MMP)-9, and scavenger receptor A. These effects of PPAR-␥ were mediated in part
by inhibition of transcription factors activator protein-1 (AP1), signal transducer and activator of transcription, and NF-␬B.
PPAR-␥ activators inhibited expression of TNF-␣, IL-6, IL-1␤
(31), iNOS, MMP-9, and scavenger receptor A in monocytes
(49). PPAR-␥ activators attenuated TNF-induced VCAM-1
and ICAM-1 expression in endothelial cells and reduced monocyte/macrophage homing to atherosclerotic plaques in apolipoprotein E-deficient mice (45). PPAR-␥ expression has indeed been demonstrated in human atherosclerotic plaques (48).
However, 15-deoxy-⌬12,14-prostaglandin (15d-PG) J2 may
stimulate the synthesis of IL-8 in endothelial cells in a PPAR␥-independent manner (32). Mechanisms whereby PPAR-␥
activation may induce anti-inflammatory effects include interactions with CCAAT/enhancer-binding protein-␦, present in
tandem repeats in the PPAR-␥ gene promoter. CCAAT/enhancer-binding protein induces expression of inflammatory
cytokines but is inhibited by PPAR-␥ in the vasculature by
transactivation (58).
PPAR-␥ activators (rosiglitazone and pioglitazone) prevented the BP rise and the structural, functional, and molecular
changes induced by ANG II in blood vessels, inhibiting cell
growth and inflammation (18). ANG II-induced small resistance artery remodeling and endothelial dysfunction were prevented. Vascular DNA synthesis, expression of cell cycle
proteins, ANG AT1 receptors, VCAM-1, and platelet and
endothelial cell adhesion molecule, and NF-␬B activity, all of
which were increased by ANG II infusion, were blunted by
pioglitazone or rosiglitazone.
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Fig. 1. Mechanism of action of peroxisome proliferatoractivated receptors (PPARs). After activation by ligand
binding, PPARs heterodimerize with retinoid X receptor
(RXR) and bind to specific PPAR response elements
(PPRE) on the promoter of target genes to regulate glucose
and lipid metabolism (right). This aspect of PPAR-␣ and
PPAR-␥ action, which has cardiovascular protective effects
through effects on atherosclerosis and diabetes, is not discussed in the present review. Left: interaction of PPAR-␣
and PPAR-␥ with different transcription factors to repress
proinflammatory genes. VCAM, vascular cell adhesion
molecule; ICAM, intercellular adhesion molecule; PECAM,
platelet and endothelial cell adhesion molecule; AP, activator protein; CCAAT/EBP, CCAAT/enhancer binding protein; CRP, C-reactive protein; MCP, monocyte chemoattractant protein; CD40L, CD40 ligand; MMP, matrix metalloproteinase; iNOS, inducible nitric oxide synthase;
VSMCs, vascular smooth muscle cells; FA, fatty acid.
CARDIAC AND VASCULAR EFFECTS OF PPARS
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A mechanism for improved endothelial function recently
reported is the ability of PPAR-␥ activators to modulate bone
marrow-derived angiogenic progenitor cells (APCs) to promote endothelial lineage differentiation and early reendothelialization after vascular intervention. Rosiglitazone treatment
attenuated neointima formation in mice after femoral angioplasty (65). Rosiglitazone caused a sixfold increase in colony
formation by human endothelial progenitor cells, promoted the
differentiation of APCs toward the endothelial lineage in
mouse bone marrow in vivo and in human peripheral blood in
vitro, and inhibited the differentiation toward the SMC lineage.
Within the neointima, rosiglitazone stimulated APCs to differentiate into mature endothelial cells and caused early reendothelialization compared with controls. Thus PPAR-␥ activators
are able to promote differentiation of APCs toward the endothelial lineage and attenuate restenosis. Elevated levels of
C-reactive protein (CRP) have been recognized as a powerful
predictor of cardiovascular disease. Verma et al. (64) demonstrated that human recombinant CRP, at pathophysiologically
relevant concentrations that predict adverse cardiovascular
outcomes, inhibits endothelial progenitor cell (EPC) differentiation, survival, and function. The effects of CRP on EPC
number, expression of endothelial cell-specific markers Tie-2,
endothelial cell-lectin, and vascular endothelial cadherin, increased EPC apoptosis, and impaired eNOS expression and
EPC-induced angiogenesis were attenuated by treatment with
rosiglitazone, which may represent a mechanism that explains,
in part, PPAR-␥ activation-induced cardioprotective effects.
VSMC proliferation is involved in vascular injury, restenosis, and atherosclerosis. Antiproliferative effects of the
PPAR-␥ agonists troglitazone, rosiglitazone, and pioglitazone
were investigated in cells derived from the internal mammary
and radial artery and saphenous veins, vessels employed for
coronary artery bypass grafting (11). The three activators of
PPAR-␥ inhibited cell proliferation, with troglitazone being the
most potent and rosiglitazone similar in potency to pioglitazone. Potency was therefore dependent on the PPAR-␥ activator independently of the vascular source of the cells.
Markers of systemic inflammation (CRP and IL-6), considered “nontraditional” risk factors for cardiovascular disease,
are enhanced in patients with Type 2 diabetes mellitus. MMP-9
may participate in atherosclerotic plaque rupture. In patients
treated with rosiglitazone for 26 wk, reductions in CRP,
MMP-9, and white blood cell count were significantly correlated with insulin resistance, as estimated by the homeostasis
model (HOMA) index, indicating potentially beneficial effects
on cardiovascular risk in this patient population (25). Another
emerging nontraditional risk factor implicated in atherosclerosis is the proinflammatory cytokine CD40 ligand (CD40L).
Diabetic patients were shown to have elevated plasma levels of
soluble CD40L (sCD40L) independent of total cholesterol,
high-density lipoprotein cholesterol, low-density lipoprotein
cholesterol, triglycerides, BP, body mass index, gender, CRP,
and soluble ICAM-1 (63). Treatment with troglitazone for 12
wk lowered sCD40L plasma levels in Type 2 diabetic patients,
suggesting a novel anti-inflammatory mechanism for limiting
diabetes-associated arterial disease. Other investigators
showed similar results in patients with Type 2 diabetes and
coronary artery disease (CAD). Thirty-nine patients with diabetes and angiographically proven CAD were treated with
rosiglitazone for 12 wk (41). Rosiglitazone, but not placebo,
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In DOCA-salt hypertensive rats, a hypertensive model associated with enhanced expression of preproendothelin (preproET)-1, BP increase was prevented in part by the PPAR-␥
activator rosiglitazone but not by the PPAR-␣ activator fenofibrate (26). Both PPAR activators, however, abrogated the
increase of prepro-ET-1 mRNA in mesenteric blood vessels of
these hypertensive rats and prevented the hypertrophic remodeling typically found in DOCA-salt rats. Rosiglitazone, but not
fenofibrate, prevented endothelial dysfunction, but both abrogated the enhanced production of reactive oxygen species that
occurs in blood vessels in DOCA-salt hypertensive rats.
Spontaneously hypertensive rats (SHR) exhibit insulin resistance, which has been associated with a mutation of cd36,
which encodes for a fatty acid translocase. Insulin resistance
thus results in decreased fatty acid translocation (1). cd36 is a
target of PPAR-␥. It has been speculated that expression of
PPARs could be decreased in blood vessels of SHR, which
would exacerbate proliferation, migration, inflammation, and
fibrosis, as found in this hypertensive model. Indeed, human
mutations of PPAR-␥ have been associated with diabetes,
insulin resistance, and hypertension, all of which are accompanied by vascular disease (4). However, rather than decreased
expression of PPAR-␣ and PPAR-␥ in blood vessels and
cultured VSMCs from SHR, their expression was increased
(20). This may result from a feedback response to the decreased activity of the mutant cd36 of SHR.
Mechanisms whereby PPAR-␥ activation improves endothelial function were investigated by Calnek et al. (8), who
demonstrated that PPAR-␥ ligands, 15d-PGJ2, or ciglitazone
increased NO release by porcine and human aortic endothelial
cells. PPAR-␥ activation did not increase eNOS expression.
Overexpression of PPAR-␥ or treatment with 9-cis-retinoic
acid also enhanced NO release. Neither 15d-PGJ2 nor ciglitazone altered eNOS mRNA. Thus PPAR-␥ ligands stimulated
NO release from endothelial cells through a transcriptional
mechanism unrelated to eNOS expression (8).
Many studies have pointed toward an inhibitory role of
PPARs in atherogenesis (40). The effect of rosiglitazone treatment on mechanisms involved in the initial stages of atherogenesis was evaluated in rabbits fed a high-cholesterol diet
(59). Treatment with rosiglitazone enhanced the downregulated PPAR-␥ expression, improved endothelium-dependent
vasodilatation, suppressed gp91phox and iNOS expression, reduced superoxide and total NO production, and inhibited
nitrotyrosine formation. The endothelial protective effects of
PPAR-␥ activators may reduce leukocyte accumulation in the
vascular wall, contributing to antiatherosclerotic effects.
Ishibashi et al. (29) studied effects of pioglitazone in rats
treated with N␻-nitro-L-arginine methyl ester to inhibit eNOS.
The PPAR-␥ activator pioglitazone did not affect BP, metabolic state, or serum NO levels but prevented N␻-nitro-Larginine methyl ester-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of
monocyte chemoattractant protein-1 but attenuated the expression of the monocyte chemoattractant protein-1 receptor C-C
chemokine receptor 2 in monocytes in the vascular wall and in
the circulation. It prevented coronary arteriosclerosis, possibly
by downregulation of C-C chemokine receptor 2, which could
represent a novel anti-inflammatory mechanism of PPAR-␥
activation independent of insulin sensitization.
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CARDIAC AND VASCULAR EFFECTS OF PPARS
CARDIAC EFFECTS OF PPARS
PPAR-␣ regulates cardiac energy and lipid metabolism and
plays a role in mitochondrial fatty acid ␤-oxidation, which is
critical for fuel generation in the heart (7). It serves as a
molecular “lipostat” through the induction of target genes
involved in fatty acid metabolism (22). PPAR-␣ controls
myocardial lipid metabolism through activation of transcripAJP-Heart Circ Physiol • VOL
tion of carnitine palmitoyltransferase I (7). In PPAR-␣-null
mice, the capacity for constitutive myocardial ␤-oxidation of
medium- and long-chain fatty acids was markedly reduced
(68). Constitutive ␤-oxidation of very-long-chain fatty acids
such as lignoceric acid was unaffected in PPAR-␣-deficient
mice. This suggests that PPAR-␣ is not involved in the constitutive expression of enzymes that mediate ␤-oxidation.
During cardiac hypertrophy, PPAR-␣ is inhibited (3), which
reduces the capacity of hypertrophied myocytes to metabolize
myocardial lipids, resulting in intracellular fat accumulation.
PPAR-␣ activators inhibited cardiac expression of TNF-␣ and
NF-␬B induced by LPS (57). Fenofibrate reduced prepro-ET-1
mRNA expression and collagen type I and type III mRNA,
associated with decreased interstitial and perivascular cardiac
fibrosis after pressure overload induced by abdominal aortic
banding (44), probably through suppression of AP-1-mediated
prepro-ET-1 gene activation. Additionally, fenofibrate reduced
cardiac hypertrophy and inflammation, associated with an
increase in the anti-inflammatory cytokine IL-10 (39). Fenofibrate had beneficial effects on inflammation and collagen
deposition in the heart of ANG II-infused rats (17). NF-␬B
activity and VCAM-1, platelet and endothelial cell adhesion
molecule, ICAM-1, and ED-1 (macrophage antigen) expression were decreased, AT1 receptors were downregulated, and
AT2 receptors were upregulated, which may be considered a
beneficial change, because AT1 receptors are prohypertrophic,
proinflammatory, and profibrotic, whereas AT2 receptors are
generally shown to exert opposite effects.
The role of PPAR-␥ in the heart is less clear than that of
PPAR-␣. Expression of PPAR-␥ in the heart is very low (33).
PPAR-␥ activators inhibited hypertrophy and brain natriuretic
peptide expression in cultured cardiomyocytes (70). Aortic
banding induced enhanced cardiac hypertrophy in heterozygous PPAR-␥-deficient mice (2), suggesting an inhibitory effect of PPAR-␥ on cardiac growth. Pioglitazone, however,
blunted myocardial hypertrophy in wild-type and PPAR-␥⫺/⫺
mice, suggesting an effect independent of activation of
PPAR-␥. ANG II-induced gene expression and cardiomyocyte
hypertrophy were attenuated in vitro by thiazolidinediones.
These data suggest that PPAR-␥ inhibits cardiac hypertrophy.
In diabetic rats, PPAR-␥ improved left ventricular diastolic
function and decreased collagen accumulation (61, 72) and
also protected the myocardium from ischemic injury (53, 71).
On the other hand, PPAR-␥ activators may trigger an aggravation of congestive heart failure (66, 69), which is counterintuitive with respect to the cardiovascular preventive potential
of these drugs. This appears to be mainly due to fluid retention
as a consequence of their insulinomimetic action on the kidney
rather than a negative inotropic effect. Thus caution has been
urged in the use of thiazolidinediones in diabetic patients with
advanced heart failure (43), even though these agents may have
cardiovascular protective properties in patients with less advanced cardiovascular disease.
The hypertrophic heart typically experiences an increase in
glucose utilization and decreased fatty acid oxidation. It is
unclear whether PPAR-␥ has effects on fatty acid metabolism
comparable to those of PPAR-␣. PPAR-␣ and PPAR-␥ have
partially overlapping ligand binding profiles. Thus PPAR-␥
may mediate some intracellular signaling in cardiomyocytes
similarly to PPAR-␣, which could attenuate cardiac remodel-
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significantly reduced sCD40L serum levels. This further underscores the ability of PPAR-␥-activating thiazolidinediones
to reduce sCD40L serum levels and exert anti-inflammatory
and antiatherogenic effects.
Rosiglitazone has also been shown to reduce endothelial
markers such as E-selectin and von Willebrand factor in
nondiabetic CAD patients (54). Eighty-four patients with stable, angiographically documented CAD without diabetes mellitus were treated with rosiglitazone for 12 wk. Rosiglitazone
significantly reduced E-selectin, von Willebrand factor, CRP,
fibrinogen, and insulin resistance, as measured by HOMA
index, compared with placebo. Thus PPAR-␥ activation reduced markers of endothelial cell activation and levels of
acute-phase reactants in CAD patients without diabetes. In
addition, other studies showed that these agents improve endothelial function of patients with the metabolic syndrome.
Wang et al. (67) studied 50 nondiabetic patients who met a
definition for the metabolic syndrome and were treated with
rosiglitazone for 8 wk. These patients experienced significant
reductions in fasting plasma insulin levels, HOMA index, BP,
and high-sensitivity CRP. Rosiglitazone treatment significantly
improved endothelium-dependent flow-mediated and endothelium-independent nitroglycerin-induced vasodilatation of the
brachial artery. Carotid intima-media thickness has been considered a surrogate of endothelial function. In 92 nondiabetic
patients with angiographically documented CAD studied by
Sidhu et al. (55), the reduction in intima-media thickness
progression after 48 wk of rosiglitazone treatment compared
with the placebo group was associated with reduced insulin
resistance (estimated by HOMA index). Thus PPAR activation
improves endothelial dysfunction, which is thought to be a
mechanism for initiation and progression of atherosclerosis, a
risk factor and a participant in the triggering of cardiovascular
events.
In a study of 136 Japanese Type 2 diabetic patients, pioglitazone was administered for 3 mo, and changes in glycolipid
metabolism, plasma high-sensitivity CRP, leptin, adiponectin,
and pulse wave velocity (PWV, a parameter that increases with
the stiffness of blood vessels and is indicative of the presence
of vascular injury) were evaluated to investigate the relation
between the antiatherogenic and antidiabetic effects of pioglitazone (51). Pioglitazone treatment improved glucose metabolism, increased plasma adiponectin concentrations, and decreased CRP and PWV. Treatment with pioglitazone was
associated with a low CRP and PWV independent of changes
in carbohydrate metabolism. Thus the PPAR-␥ agonist exerted
antiatherogenic effects independent of its antidiabetic action by
lowering CRP, which contributes to vascular injury and the
stiffness of blood vessels (a measure of vascular disease) and
contributes to enhanced pulse pressure (another risk factor for
vascular events).
CARDIAC AND VASCULAR EFFECTS OF PPARS
CONCLUSION
PPAR-␣ and PPAR-␥ modulate inflammatory, fibrotic, and
hypertrophic responses in the cardiovascular system. The signaling pathways mediating the anti-inflammatory effect of
PPARs, particularly in the heart, remain to be demonstrated.
The contrast between the beneficial effect of PPAR-␥ activators on the heart in experimental models and clinical reports of
decompensated heart failure in some diabetic patients treated
with PPAR-␥ activators requires clarification. It is possible that
salt and water retention induced by the insulin-sensitizing
action of PPAR-␥ activators unmasks latent left ventricular
dysfunction and precipitates heart failure not directly induced
by actions of PPAR-␥ activators on the heart (66). Selective
PPAR-␣ or PPAR-␥ activators, partial agonists or dual ␣/␥activators, may become interesting cardiovascular protective
therapies in hypertension or other forms of cardiovascular
disease in the near future.
GRANTS
Work from the author’s laboratory has been supported by Canadian Institutes of Health Research Grants 13570 and 37917 and a group grant to the
Multidisciplinary Research Group on Hypertension.
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