Effects of rosuvastatin on fasting and postprandial lipoprotein and fatty acid metabolism in combined hyperlipidemic male patients with premature coronary sclerosis

DISCOVERY: a comparison of efficacy and safety of rosuvastatinand atorvastatin in high-risk subjects with hypercholesterolaemia

T. E. STRANDBERG,1 J . FEELY2 AND E. L. SIGURDSSON3

Helsinki University Central Hospital,1 Helsinki, Finland, St James’s Hospital,2 Dublin, Ireland, Health Care Centre

Solvangur,3 Hafnarfjordur, Iceland

In clinical practice, many patients fail

to achieve lipid levels recommended by

guidelines for the prevention of coron-

ary heart disease. Consequently, more

effective lipid-modifying therapies are

required. DISCOVERY was a 12-

week, parallel-group, open-label, ran-

domised, multicentre study comparing

rosuvastatin (RSV) with atorvastatin

(ATV) on changes in lipid levels and

the achievement of European lipid

goals. Patients (� 18 years) with high

cardiovascular risk and low-density

lipoprotein cholesterol (LDL-C) levels

> 3.5 mmol/l from primary care prac-

tices and hospital centres were rando-

mised (2:1) to receive treatment with

RSV 10 mg/day (n ¼ 627) or ATV

10 mg/day (n ¼ 284). Statin-naıve

subjects had a 6-week dietary period

before randomisation, whereas patients

with LDL-C> 3.1 mmol/l on another

statin treatment were switched to the

study drug immediately. Lipid levels

were assessed at baseline and after 12

weeks. Baseline lipid levels and patient

demographics were similar between

treatment groups. More patients

achieved LDL-C goals with RSV com-

pared with ATV (Table). Both the

agents were well tolerated. RSV

(10 mg/day) treatment for 12 weeks

was significantly more effective than

ATV (10 mg/day) at lowering LDL-C

and enabled more patients in a high-

risk primary care population to achieve

recommended lipid goals.

Rosuvastatin has greater beneficial effects than atorvastatin onLDL-C, HDL-C and apolipoproteins A-I and B in subjects with themetabolic syndrome

A. F. H. STALENHOEF, ON BEHALF OF THE COMETS STUDY INVESTIGATORS

University Medical Centre Nijmegen, Nijmegen, the Netherlands

COMETS (4522IL/0069) compared

the efficacy of rosuvastatin (RSV)

with atorvastatin (ATV) and placebo

in patients with the metabolic syn-

drome. The primary end point was

low-density lipoprotein cholesterol

(LDL-C) reduction; other lipid assess-

ments included high-density lipo-

protein cholesterol (HDL-C),

apolipoprotein (apo) A-I, apo B and

the apo B/apo A-I ratio. After a

4-week dietary lead-in period, statin-

naıve metabolic syndrome patients

(NCEP ATP III definition), with

LDL-C � 3.36 mmol/l (130 mg/dl),

additional multiple risk factors confer-

ring a 10-year coronary heart disease

(CHD) risk> 10% but no evidence of

CHD or other atherosclerotic disease

or overt diabetes, were randomised

(2:2:1) to receive RSV 10 mg, ATV

10 mg or placebo for 6 weeks,

subsequently followed by RSV 20 mg,

ATV 20 mg or RSV 20 mg, respectively,

for 6 weeks. At 6 and 12 weeks,

percentage change from baseline in lipids

were compared across treatment groups

by ANOVA. RSV provided significantly

greater LDL-C lowering and signif-

icantly improved HDL-C and the

apolipoprotein profile compared with

ATV and placebo. All treatments were

well tolerated.

Patients at LDL-C goal (%)

Mean change in LDL-Cfrom baseline (%)*

1998 European goals(< 3 mmol/l)

2003 European goals(< 2.5 mmol/l)

RSV (10 mg/day) �48.6 83.4 73.2

ATV (10 mg/day) �40.6† 68.3‡ 52.5‡

ATV, atorvastatin; LDL-C, low-density lipoprotein cholesterol; RSV, rosuvastatin; *Statin-naıve patients

only (n ¼ 761); †p< 0.05 vs. RSV; ‡p< 0.001 vs. RSV.

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59 (Suppl. 148), 3–13

ABSTRACTS

Effects of rosuvastatin and atorvastatin on LDL-C, andapolipoproteins A-I and B in patients with type 2 diabetes: resultsof the URANUS study

C. BERNE1 AND A. SIEWERT-DELLE2 ON BEHALF OF THE URANUS STUDY INVESTIGATORS

Medicincentrum,1 Akademiska Sjukhuset, Uppsala, Sweden, AstraZeneca Sverige AB,2 Sodertalje, Sweden

The URANUS study (4522SE/0001)

compared the efficacy of rosuvastatin

(RSV) 10–40 mg with atorvastatin

(ATV) 10–80 mg in patients with

type 2 diabetes. The primary end

point was low-density lipoprotein cho-

lesterol (LDL-C) reduction; other lipid

assessments included apolipoprotein

(apo) A-I, apo B and the apo B/apo

A-I ratio. After a 6-week dietary lead-

in period, 469 adult patients with

LDL-C � 3.3 mmol/l were rando-

mised (1:1 blinded) to RSV 10 mg or

ATV 10 mg for 4 weeks; doses were

then up-titrated at 4-weekly intervals

for 12 weeks (up to RSV 40 mg or

ATV 80 mg) to achieve the 1998

European LDL-C goal of< 3.0 mmol/l

for patients with diabetes. At 4 and

16 weeks, changes from baseline in lipid

parameters were compared across treat-

ment groups by ANCOVA. RSV provided

significantly greater LDL-C lowering and

improved the apolipoprotein profile

significantly more than ATV at initial

doses (4 weeks), and after titration

(16 weeks). All treatments were well

tolerated.

In conclusion, RSV improved LDL-C

and the apolipoprotein profile signif-

icantly more than ATV in patients with

diabetes and dyslipidaemia.

Least-squares mean change from baseline (%)

6 weeks 12 weeks

RSV 10 mg(n ¼164)

ATV 10 mg(n ¼155)

Placebo(n ¼78)

RSV 10/20 mg andplacebo/RSV 20 mg (n ¼242)

ATV 10/20 mg(n ¼155)

LDL-C �41.7 �35.7* �4.1* �48.7 �42.7*

HDL-C þ9.3 þ4.8† þ2.2* þ10.5 þ5.7†

Apo A-I þ5.9 þ1.2* þ1.8† þ6.2 þ3.2‡

Apo B �34.1 �30.7‡ �3.3* �40.7 �36.0†

Apo B/apo A-I ratio �37.1 �30.9* �4.3* �43.6 �37.5*

ATV, atorvastatin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RSV, rosuvastatin; *p< 0.001, ‡p< 0.05,

†p< 0.01 vs. RSV at same time point.

Least-squares mean change from baseline (%)

4 weeks 16 weeks

RSV 10 mg(n ¼ 232)

ATV 10 mg(n ¼ 231)

RSV 10–40 mg(n ¼ 221)

ATV 10–80 mg(n ¼ 220)

LDL-C �47.6* �38.5§ �52.3* �45.5

Apo A-I þ2.6† þ0.8 þ2.6‡ �0.2

Apo B �42.9* �35.3 �45.2* �40.1

Apo B/apo A-I �43.9* �35.4 �46.3* �39.6

Apo A, apolipoprotein A; ATV, atorvastatin; LDL-C, low-density lipoprotein cholesterol; RSV, rosuvastatin; *p< 0.001, †p ¼ 0.05, ‡p< 0.01 vs. ATV at same

time point, §n ¼ 232.

4 XV INTERNATIONAL SYMPOSIUM, DALM 2004


LDL-C/HDL-C ratio in patients with coronary artery disease andlow HDL-C: the RADAR study

J . W. JUKEMA AND A. H. LIEM, ON BEHALF OF THE RADAR STUDY INVESTIGATORS

Department of Cardiology, Leiden University Medical Center, the Netherlands

Low levels of high-density lipoprotein

cholesterol (HDL-C) are a risk factor

for coronary artery disease (CAD) and

the low-density lipoprotein cholesterol

(LDL-C)/HDL-C ratio is a powerful

predictor of clinical events. RADAR

was a randomised, multicentre, parallel-

group study that compared the effect of

rosuvastatin (RSV) with atorvastatin

(ATV) on lipid levels in patients

with CAD and low HDL-C levels.

Following dietary lead-in, 461 patients

aged 40–80 years with established

atherosclerotic disease and HDL-C

< 1 mmol/l were randomised to

receive RSV 10 mg (n ¼ 230) or ATV

20 mg (n ¼ 231). Patients were

forced-titrated at 6 weeks (RSV 20 mg,

ATV 40 mg) and 12 weeks (RSV

40 mg, ATV 80 mg) (18 weeks

total treatment). Baseline LDL-C

(mean � SD) was 3.6 � 1.2 mmol/l

(RSV) and 3.7 � 1.3 mmol/l (ATV)

and HDL-C, 0.8 � 0.1 mmol/l (RSV)

and 0.8 � 0.1 mmol/l (ATV). RSV

reduced LDL-C and the LDL-C/

HDL-C ratio (Table) more than ATV.

Furthermore, significantly more patients

achieved 2003 European LDL-C goals

(< 2.5 mmol/l) with RSV compared

with ATV after 18 weeks (RSV 93.9%

vs. ATV 85.3%; p< 0.01). Both the

treatments were well tolerated. In

conclusion, RSV is more effective than

ATV at reducing LDL-C and improving

the LDL-C/HDL-C ratio and thereby

enabling more patients with CAD and

low HDL-C levels to achieve their

LDL-C goal.

Effects of rosuvastatin on fasting and postprandial lipoproteinand fatty acid metabolism in combined hyperlipidemic malepatients with premature coronary sclerosis

A. VAN OOSTROM,1 T. PLOKKER2 AND M. C. CABEZAS1 ,3

Department of Internal Medicine,1 University Medical Center Utrecht, Utrecht, the Netherlands, Department of

Cardiology,2 St Antonius Hospital, Nieuwegein, the Netherlands, Department of Internal Medicine,3 St Franciscus Hospital,Rotterdam, the Netherlands

Postprandial hyperlipidemia is asso-

ciated with premature coronary artery

disease (CAD) and can improve by

statins. We investigated the effects of

rosuvastatin on postprandial lipopro-

tein and fatty acid metabolism in

20 male premature CAD patients

(50 � 4 years). Self-determined day-

long capillary triglycerides (TGc) were

Least squares mean change from baseline (%)

6 weeks 12 weeks 18 weeks

RSV 10 mg ATV 20 mg RSV 20 mg ATV 40 mg RSV 40 mg ATV 80 mg

LDL-C/HDL-C ratio �47.0* �41.9 �53.0† �47.9 �57.3‡ �49.6

LDL-C �44.0* �38.4 �50.4† �45.1 �55.3‡ �48.1

TC �37.4§ �32.5 �41.1‡ �37.3 �44.7§ �39.5

HDL-C þ3.9 þ4.1 þ5.5 þ3.1 þ4.7 þ2.7

ATV, atorvastatin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RSV, rosuvastatin; TC, total cholesterol; *p< 0.05,

†p< 0.01, ‡p< 0.001, §p< 0.0001 vs. ATV at the same time point.

XV INTERNATIONAL SYMPOSIUM, DALM 2004 5


measured off-treatment and after rosu-

vastatin 20 and 40 mg/day.

Standardised oral fat-loading tests

(OFLT) were performed off-treatment

and after 40 mg/day. Twenty age- and

waist-matched healthy controls served

as a reference group. Rosuvastatin

20 mg/day improved fasting low-

density lipoprotein (LDL)-cholesterol,

plasma TG, apolipoprotein B and

high-density lipoprotein (HDL)-

cholesterol (�52, �37, �37 and

þ25%, p< 0.01 each). Total daylong

triglyceridemia (TGc-AUC, area under

the TGc-curve) was reduced by 33%

(p< 0.001), but remained higher than

in the reference group. Rosuvastatin

40 mg/day did not show significant

additional effects on fasting lipids and

daylong TGc. Tested by OFLT, rosu-

vastatin 40 mg/day reduced plasma

TG-AUC by 23% (p< 0.005), reach-

ing reference values. Whereas strong

and significant reductions in the fasting

and postprandial cholesterol content of

chylomicron, VLDL1 and VLDL2

fractions were achieved, the TG reduc-

tion in these lipoproteins was less

pronounced. Furthermore, rosuvastatin

normalised postprandial complement

component 3 and hydroxybutyric acid

changes, indicative of improved peri-

pheral fatty acid (FA) trapping and

reduced hepatic FA flux. In conclusion,

in combined hyperlipidemic patients

with premature CAD, rosuvastatin

improves postprandial FA and lipopro-

tein metabolism, the latter by strongly

reducing the cholesterol content of TG-

rich lipoproteins. These pleiotropic

effects of rosuvastatin contribute to

CAD risk reduction.

Achievement of apolipoprotein B goal in patients who achievetheir low-density lipoprotein cholesterol goal: results of theMERCURY I trial

P. J . BARTER,1 C. WATKINS2 AND D. KALLEND,2 FOR THE MERCURY I TRIALIST GROUP

Heart Research Institute,1 Sydney, Australia, AstraZeneca,2 Cheshire, UK

Apolipoprotein B (apo B) is the major

apolipoprotein in all atherogenic lipo-

proteins. A total apo B goal has been

recommended as a secondary target

after the appropriate low-density

lipoprotein cholesterol (LDL-C) goal

has been met. This multinational

trial (4522IL/0081) assessed the

efficacy of rosuvastatin to bring

hypercholesterolemic patients with

coronary heart disease, atherosclerosis

or type 2 diabetes and fasting LDL-C

� 2.99 mmol/l (� 115 mg/dl) to these

primary and secondary endpoints when

switched from atorvastatin, simvastatin

Period 1(weeks 0–8)

Period 2(weeks 9–16)

Percentage of patients achievingLDL-C goal* at week 16

Percentage of patients achievingLDL-C* þ apo B† goals at week 16

RSV10 (n ¼ 538) RSV10 (n ¼ 521) 79 50

ATV10 (n ¼ 529) ATV10 (n ¼ 240)

RSV10 (n ¼ 276)

69

79‡

34

49‡

ATV20 (n ¼ 925) ATV20 (n ¼ 299)

RSV10 (n ¼ 293)

RSV20 (n ¼ 305)

74

78

86‡

46

50

62‡

SIM20 (n ¼ 543) SIM20 (n ¼ 250)

RSV10 (n ¼ 277)

60

75‡

29

45‡

PRA40 (n ¼ 521) PRA40 (n ¼ 253)

RSV10 (n ¼ 253)

50

80‡

24

53‡

ATV, atorvastatin; PRA, pravastatin; SIM, simvastatin; RSV, rosuvastatin.

*< 160 mg/dl,< 130 mg/dl and< 100 mg/dl for low-, medium- and high-risk patients, respectively (Adult Treatment Panel III. JAMA 2001;285:2486–97),

†< 130 mg/dl,< 110 mg/dl and< 90 mg/dl for low-, medium- and high-risk patients, respectively (Grundy SM. Circulation 2002;106:2526–9), ‡p< 0.001,

RSV10 vs. ATV10, SIM20 or PRA40 and RSV20 vs. ATV20.



or pravastatin. After a 6-week dietary

lead-in, 3140 adults were randomised to

open-label rosuvastatin 10 mg (RSV10),

atorvastatin 10 mg (ATV10), atorvastatin

20 mg (ATV20), simvastatin 20 mg

(SIM20) or pravastatin 40 mg (PRA40)

for 8 weeks. Patients then stayed on these

treatments or switched for 8 more week

from ATV10, SIM20 and PRA40 to

RSV10 or from ATV20 to RSV10 or

rosuvastatin 20 mg (RSV20). Table

summarises week-16 comparisons of

percentage of patients achieving LDL-C

and apo B goals (all risk categories

combined) using logistic regression

analyses.

Over 16 weeks, all treatments were

well tolerated, with similar adverse

event types and occurrence rates among

treatment groups. There were no cases of

myopathy. Switching to rosuvastatin

from comparator statins at the

doses studied brought more patients,

including those at high risk of coronary

artery disease, to their primary LDL-C

and secondary total apo B treatment

goals.

Undertreatment among high-risk dyslipidemic patients:results of a national survey of goal achievement for NationalCholesterol Education Program Adult TreatmentPanel III guidelines

M. H. DAVIDSON,1 , 2 K. C. MAKI,1 T. A. PEARSON3 AND R. C. PASTERNAK,4 FOR THE NEPTUNE

STEERING COMMITTEE AND INVESTIGATORS

Radiant Development,1 Rush University Medical Center,2 Chicago, IL, University of Rochester School of Medicine,3 Rochester, NY,

Massachusetts General Hospital,4 Boston, MA, USA

The Lipid Treatment Assessment

Program, a national survey of physician

compliance with National Cholesterol

Education Program Adult Treatment

Panel (NCEP ATP) guidelines (com-

pleted in 1997), showed significant

underachievement of ATP II low-

density lipoprotein cholesterol (LDL-C)

goals. NCEP Evaluation ProjecT

Utilizing Novel E-technology

(NEPTUNE) II was designed to estimate

the probability of achieving NCEP ATP

III cholesterol treatment goals in patients

with treated dyslipidemia. A US sample

of very high prescribers of lipid-modify-

ing medications (n ¼ 376: 83% primary

care physicians; 17% cardiologists or

endocrinologists) was asked to enroll 10

or 20 consecutive patients. Patient data

were recorded using NEPTUNE II software

on a Personal Digital Assistant and

uploaded to a central database via the

Internet. The number and percentage of

patients in each risk category who

achieved their LDL-C or LDL-C plus

non-high-density lipoprotein cholesterol

(non-HDL-C) treatment goals are shown

below.

These results suggest improved com-

pliance with LDL-C goals among very

high prescribers of lipid-modifying

therapies since 1997. However, a sig-

nificant proportion of high-risk

patients, especially those with elevated

non-HDL-C due to hypertriglyceride-

mia, remain undertreated.

0–1 risk factor 2þ risk factors CHD þ CHD RE Total

LDL-C goal (mg/dl) < 160 < 130 < 100 –

Number of patients 859 1318 2708 4885

Percentage of patients who

achieved LDL-C goal (95% CI)

89 (86.91) 76 (73.78) 57 (55.58) 67 (66.69)

Non-HDL-C goal (mg/dl) < 190 < 160 < 130 –

Number of patients 163 340 728 1231

Percentage of patients who achieved

both LDL-C and non-HDL-C goals (95% CI)*

64 (57.72) 52 (47.57) 27 (24.30) 39 (36.42)

CHD, coronary heart disease; CHD RE, CHD risk equivalents; CI, confidence intervals; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density

lipoprotein cholesterol; *Goals in patients with triglycerides � 200 mg/dl.



The antioxidant defence protein heme oxygenase-1 is a noveltarget site for rosuvastatin in endothelial cells

N. GROSSER,1 A. HEMMERLE,1 G. BERNDT,1 U. HINKELMANN,1 G. SMITH2 AND H. SCHRODER1

Department of Pharmacology and Toxicology,1 School of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany,AstraZeneca,2 Macclesfield, Cheshire, UK

Cholesterol-independent, pleiotropic

actions of 3-hydroxy-3-methylglutaryl

coenzyme A reductase inhibitors (sta-

tins) lead to anti-inflammatory and

antioxidant actions by mechanisms

which are currently not clearly under-

stood. Heme oxygenase-1 (HO-1) has a

central role in cellular antioxidant

defence and tissue-protective action.

This study explores the potential-

protective role of rosuvastatin on HO-1

as a regulatory target in vascular dys-

function. In cultured endothelial cells

derived from human umbilical vein,

rosuvastatin (3–100 mM) increased

HO-1 mRNA and protein levels in a

concentration-dependent fashion.

HO-1 induction by rosuvastatin

remained unaffected by mevalonate and

nitro-L-arginine-methyl ester (L-NAME),

precluding the involvement of isoprenoid-

and nitric oxide-dependent pathways.

Pretreatment of endothelial cells with

rosuvastatin, at concentrations that were

also effective at raising HO-1, reduced

nicotinamide adenine dinucleotide

phosphate (NADPH)-dependent pro-

duction of oxygen radicals. Antioxidant

activity in endothelial cells persisted after

rosuvastatin had been removed from the

incubation medium. The HO-1 meta-

bolite bilirubin, when added exogenously

to the cells at low micromolar

concentrations, virtually abolished

NADPH-dependent oxidative stress.

Rosuvastatin-induced inhibition of free

radical formation was rescued in the

presence of the HO inhibitor, tin

protoporphyrin-IX (SnPP). Our results

demonstrate that HO-1 is a target site

and antioxidant mediator of rosuvastatin

in endothelial cells. This novel pathway

may contribute to and in part, explain

the pleiotropic anti-inflammatory and

antiatherogenic actions of rosuvastatin.

Rosuvastatin reduced cell death through reduction of caspase-3activity and up-regulation of a-secretase in human neuroblastomaSH-SY5Y cells exposed to b-amyloid (1–42)

D. FAMER AND M. CRISBY

Neurotec Department, Division of Geriatric Medicine, Section for Clinical Geriatrics, Karolinska Institutet, Karolinska University

Hospital, Huddinge, Stockholm, Sweden

Accumulating evidence suggests that

disturbances in cholesterol metabolism

in the brain, as well as in the peripheral

tissues, potentiate the formation and

deposition of b-amyloid (Ab) and the

progression of Alzheimer’s disease

(AD). Statins have been shown to

decrease cholesterol synthesis through

competitive inhibition of 3-hydroxy-3-

methylglutaryl coenzyme A (HMG-

CoA) reductase. We have studied the

effect of rosuvastatin on cell death, espe-

cially caspase-3 activity, a key effector of

the caspase cascade during apoptosis in

human neuroblastoma SH-SY5Y cells,

and evaluated the effect of rosuvastatin

on the activity of a-secretase, a key

enzyme in the processing of Ab.Pretreatment of cells with rosuvastatin

prior to exposure to Ab1�42 resulted in

a significant decrease in caspase-3 activ-

ity (approximately 53%, p ¼ 0.016)

compared to cells treated with Ab1�42

alone. The reduction in caspase-3 activ-

ity was reversed by co-incubation with

mevalonate (approximately 64%,

p ¼ 0.013). Exposure of cells to

Ab1�42 alone or to rosuvastatin alone

had little or no effect on a-secretaseactivity compared to control cells.

Pretreatment with rosuvastatin prior to

exposure to Ab1�42 significantly

increased a-secretase activity (approxi-

mately 99%, p ¼ 0.014) compared

with control cells, while co-incubation

ofmevalonate reversed the effect of rosu-

vastatin on a-secretase activity. This is,to our knowledge, the first report that

demonstrates that rosuvastatin has neu-

roprotective activity in human neuro-

blastoma SH-SY5Y cells exposed to

Ab1�42. The protective effect is

mediated through the inhibition of

caspase-3 activity and up-regulation of

a-secretase activity.



Rosuvastatin provides anti-inflammatory effects and end-organprotection in stroke-prone rats

L. SIRONI, P. GELOSA, E. GIANAZZA, U. GUERRINI, E. NOBILI , A. GIANELLA, B. CREMONESI,

R. PAOLETTI AND E. TREMOLI

Department of Pharmacological Sciences, University of Milan, Milan, Italy

Spontaneously hypertensive stroke-

prone rats (SHRSP) develop brain

abnormalities, preceded by systemic

inflammation characterised by the accu-

mulation, in the serum and urine, of

several acute-phase proteins. Thus, this

experimental model represents a useful

tool to evaluate inflammation in the

context of brain injury. We investigated

whether rosuvastatin influences the

development of inflammation asso-

ciated with brain abnormalities in salt-

loaded SHRSP. SHRSP, fed a high-salt

diet, were treated long-term with vehicle

or rosuvastatin (1 and 10 mg/kg/day).

Brain abnormalities developed after

40 � 5 and 60 � 5 days (p< 0.05) of

salt-loading in the vehicle- and rosuvas-

tatin-treated (1 mg/kg/day) SHRSP,

respectively. After 100 days of treat-

ment, no damage was detectable in

30% of the rats treated with the highest

dose of drug. Rosuvastatin treatment

attenuated the expression of MCP-1,

TGF- b1, IL-1b and TNF-a in the kid-

ney and of P-selectin in brain vessels.

Furthermore, rosuvastatin treatment

increased the mRNA expression of

endothelial nitric oxide synthase in the

aorta, as compared with vehicle-treated

SHRSP. Urinary excretion of acute-

phase proteins increased in vehicle-

treated but remained negligible in the

drug-treated animals. These effects are

independent of changes in cholesterol

levels or other physiological parameters

such as blood pressure. Treatment of

SHRSP with simvastatin (2–20 mg/

kg/day) did not exert any protective

effects in this animal model. Our

observations support the hypothesis

that rosuvastatin represents a novel

means of attenuating inflammatory pro-

cesses associated with cerebrovascular

disease.

Antithrombotic and anti-inflammatory properties ofrosuvastatin in cultured human endothelial cells

L. MUSSONI,1 S . COLLI,1 M. BRAMBILLA,1 A. BANAS,1 S . ELIGINI,1 M. CAMERA1 ,2 AND

E. TREMOLI1 , 2

Department of Pharmacological Sciences,1 University of Milan, Centro Cardiologico Monzino IRCCS,2 Milan, Italy

Rosuvastatin (RSV) is a new 3-hydroxy-

3-methylglutaryl coenzyme A reductase

(HMG-CoA) inhibitor with distinct

physicochemical, pharmacokinetic and

pharmacologic properties. It is rela-

tively hydrophilic with a plasma half-

life of about 20 h and, besides plasma

low-density lipoprotein (LDL)-choles-

terol level reduction, it lowers triglycer-

ides and increases high-density

lipoprotein (HDL)-cholesterol in

patients with mixed dyslipidemia or

hypertriglyceridemia. Statins, independ-

ently of their lipid lowering effect,

modulate several mechanisms that are

involved in the atherothrombotic

process. In the present study, we evalu-

ated the effect of RSV on plasminogen

activator inhibitor-1 (PAI-1) and tissue

factor (TF) in cultured human umbilical

vein endothelial cells (HUVEC).

Moreover, the capacity of the drug to

control inflammation was assessed

through the evaluation of endothelial

nitric oxide synthase (eNOS) and

Cox-2 levels. RSV, concentration-

dependently (10–100 mM) reduced

PAI-1 antigen, either secreted or

stored in resting HUVEC (10 mMRSV: �68%, p< 0.01). In contrast,

TF activity induced by TNF-a was scar-

cely affected, even at the highest

concentration used (100 mM). eNOS

levels, detected by Western blot analysis,

were increased by RSV in a concentra-

tion-dependent fashion (25 mM RSV:

þ76%, p< 0.05). In addition, the

drug reduced Cox-2 synthesis induced

by phorbol myristate acetate (PMA)

(10 mM RSV: �46%, p< 0.01). Meva-

lonate (100 mM) added concomitantly

with RSV prevented all these effects.

None of the treatment conditions used

resulted in substantial changes in cell

morphology. In conclusion, the decrease

of PAI-1 antigen levels coupled with

eNOS up-regulation in resting

endothelial cells is promising for the



antithrombotic profile of the drug.

Moreover, the inhibition of COX-2

synthesis in stimulated endothelial cells

points to a protective effect of RSV in the

development of the inflammatory reaction

that takes place in atherothrombosis.

Rosuvastatin reduces inflammation and atherothrombosis inapoE-deficient mice

M. CANAVESI ,1 M. MONETTI,1 M. CAMERA,2 R. PARENTE,1 R. BONZI,2 R. PAOLETTI,1

E. TREMOLI,2 A. CORSINI1 AND S. BELLOSTA1

Department of Pharmacological Sciences, University of Milan,1 Monzino Cardiology Center IRCCS,2 Milan, Italy

Statins have been shown to possess sev-

eral antiatherogenic properties indepen-

dent of cholesterol lowering in

experimental settings. Based on these

premises, we investigated the anti-

inflammatory and antiatherothrombotic

properties of rosuvastatin in apoE-defi-

cient female mice. Animals were fed a

cholesterol-rich (HC) diet containing

rosuvastatin (0, 1, 2 or 10 mg/kg/day;

n ¼ 9 mice per group) for 12 weeks.

Treatment with rosuvastatin did not

significantly alter either body-weight

gain or plasma total cholesterol (C)

and triglyceride levels compared to con-

trol animals. However, rosuvastatin

treatment dose-dependently reduced

ICAM-1 expression in the aortic valves

(V) (up to 40% inhibition, p< 0.01)

and in the proximal segment of the

ascending aorta (AA) (up to 50%,

p< 0.001). Similarly, rosuvastatin

inhibited VCAM-1 expression in the

V (up to 40%, P< 0.01) and in the

AA (up to 35%, p< 0.01). Moreover,

these inhibitory effects of rosuvastatin

on the expression of adhesion mole-

cules led to a reduced accumulation of

macrophages in the V in a dose-depen-

dent and statistically significant manner

(�50%, p< 0.001). These anti-inflam-

matory effects were reflected in a

dramatic reduction of cholesterol

deposition in the entire aorta, both in

the free and in the esterified form

(free �50%; esterified �70%), with

an increase in the ratio between free

C/esterified C. Finally, the expression

of tissue factor, the most potent pro-

thrombogenic agent, increased after

starting the HC diet but was consis-

tently reduced in AA by rosuvastatin

treatment (�71%, p< 0.001) even at

the lowest dose. Altogether, the data

demonstrate that rosuvastatin has

anti-inflammatory and antiathero-

thrombotic activities beyond its

plasma cholesterol-lowering effect in

apoE-deficient mice that could trans-

late into a beneficial effect in

atherogenesis.

Rosuvastatin enhances arteriogenesis in a murine disease modelof apoE–/– deficiency

I . HOEFER,1 F. HEDWIG,1 B. MEDER,1 S. ULUSANS,1 C. BERGMANN,1 S. FISCHER,1 N. VAN ROYEN2

AND I. BUSCHMANN1

Research Group for Arteriogenesis,1 Department of Cardiology, University of Freiburg, Germany, Academic Medical

Center,2 Department of Cardiology, University of Amsterdam, The Netherlands

Recruitment, proliferation and growth of

pre-existent arteriolar anastomoses to

functional collateral arteries (arteriogen-

esis) serves as an efficient mechanism to

prevent devastating consequences of

atherosclerotic vessel occlusion. Current

pharmaceutical treatment options for

atherosclerosis focus on improving the

lipid profile by lowering LDL-cholesterol

levels through 3-hydroxy-3-methylglu-

taryl coenzyme A reductase inhibitors

(statins). Because both arteriogenesis

and cholesterol-lowering act together in

the improvement of the clinical outcome,

we tested the effect of rosuvastatin, the

most effective statin to date, on arterio-

genesis. Seventy-two apoE–/– mice

received either PBS (control) or rosuva-

statin (10 mg/kg) subcutaneously once

daily after ligation of the right femoral

artery. Following 7 days or 6 months of



rosuvastatin treatment, hind-limb

perfusion was assessed using fluorescent

microspheres. Blood was collected for

evaluation of circulating endothelial

progenitor cells (EPC). Histological

tissue specimens of the hind limb and

the aortic arch were taken, and the

atherosclerotic plaque area of the aorta

was quantified. Rosuvastatin treatment

significantly decreased the aortic

atherosclerotic plaque area and improved

plaque composition. The amount of

circulating EPC was not affected by the

treatment. Hind-limb perfusion was

significantly enhanced by rosuvastatin

7 days after femoral ligation

(PBS: 26.6 � 5.3%, rosuvastatin:

35.3 � 3.7% of normal; p< 0.001)

and retained a greater level of

improvement after 6 months (PBS:

49.1 � 6.1%, rosuvastatin: 56.0 �5.6%; p< 0.05). We have previously

demonstrated the importance of mono-

cyte-induced arteriogenesis at the sites of

vascular ischemic damage. Quantitative

immunohistology revealed an improved

migratory ability of monocytes to the site

of collateral artery growth. Rosuvastatin

positively modulates arteriogenesis in

atherosclerotic apoE–/– mice, in the

absence of mobilisation of EPC.

Rosuvastatin also reduced the athero-

sclerotic burden in these mice.

Rosuvastatin attenuates hypertension-induced cardiovascularremodelling without affecting blood pressure in DOCA-salthypertensive rats

D. LOCH,1 A. HOEY2 AND L. BROWN1

School of Biomedical Sciences,1 University of Queensland, Centre for Biomedical Research,2 University of Southern Queensland,

Australia

Pleiotropic effects of statins represent

potential novel mechanisms for the treat-

ment of hypertension, cardiovascular

remodelling and heart failure. We have

investigated cardiac remodelling in

deoxycorticosterone acetate (DOCA)-

salt hypertensive rats treated with rosuva-

statin (RSV). Male 8-week-old Wistar

rats were uninephrectomised and treated

with DOCA (25 mg every fourth day sc)

and 1%NaCl in their drinking water for

4 weeks; uninephrectomised (UNX) rats

served as controls. R-treatment groups

received 20 mg/kg/day R in 10%

Tween 20 by oral gavage for 32 days

commencing 4 days before uninephrect-

omy. R did not alter systolic blood pres-

sure but decreased left ventricular weight

relative to body weight compared with

DOCA rats (DOCA 3.05 � 0.10 and

DOCA þ RSV 2.68 � 0.10 mg/kg;

UNX 1.81 � 0.04 and UNX þ RSV

1.92 � 0.04 mg/kg). Diastolic stiffness

was increased inDOCA rats, but lowered

from 24.9 � 0.4 (DOCA, n ¼ 12) to

21.5 � 0.5 by RSV (DOCA þ RSV,

n ¼ 7), while UNX rats remained

unchanged (UNX 21.4 � 0.4

and UNX þ RSV 21.9 � 0.4). The

left ventricular interstitial collagen

content (DOCA 4.39 � 0.59 and

DOCA þ RSV 2.61 � 0.39% area;

UNX 2.58 � 0.16 and UNX þ RSV

2.38 � 0.31% area) was reduced to

control levels in DOCA-salt rats treated

with RSV. Drug treatment failed to alter

aortic media thickening observed in

DOCA-salt rats (DOCA: 105.6

� 2.8 mm and UNX: 84.7 � 1.8 mm).

Action potential duration at 90% of

repolarisation from microelectrode

recordings of isolated papillary muscle

preparations was reduced from 114.4 �3.3 to 95.2 � 3.1 msec with RSV

treatment in DOCA-salt rats

(UNX 45.99 � 0.99 and UNX þ RSV

51.36 � 3.91 msec). RSV shows a

marked beneficial effect by attenuating

increases in cardiac stiffness and collagen

deposition, and also, both cardiac

hypertrophy and action potential

prolongation in the DOCA-salt model

of hypertension in rats without altering

systolic blood pressure.



Rosuvastatin prevents cardiovascular remodelling withoutlowering blood pressure in ageing male spontaneouslyhypertensive rats

D. LOCH AND L. BROWN

School of Biomedical Sciences, University of Queensland, Australia

Statins exert direct beneficial effects

on cardiovascular remodelling, hyper-

tension and heart failure, which are inde-

pendent of their intrinsic cholesterol-

lowering ability. This project investigated

cardiac remodelling and heart failure

in ageing spontaneously hypertensive

rats (SHR) treated with rosuvastatin

(RSV, 20 mg/kg/day) by oral gavage

for 24 weeks, commencing at 15 months

of age. Age-matched Wistar Kyoto

(WKY) rats served as controls (n � 6/

group) (*p< 0.05 vs. untreated). RSV

did not alter systolic blood pressure

(SHR 200 � 6, SHR þ RSV190 � 8;

WKY 148 � 7 and WKY þ RSV

159 � 2 mmHg) but decreased

left ventricular weight/body weight

ratio in SHR (SHR 4.09 � 0.10,

SHR þ RSV 3.50 � 0.13*; WKY

2.29 � 0.05 and WKY þ RSV

2.14 �0.05 mg/kg). Thoracic aorta

media width was unaltered with treat-

ment (SHR 146.0 � 4.2, SHR þRSV 142.6 �4.3; WKY 106.1 �2.1, WKY þ RSV 99.8 � 2.1 mm).

Diastolic stiffness was lowered from

33.1 � 0.8 (SHR) to 27.5 � 0.6*

(SHR þ RSV), while WKY rats were

unchanged (WKY 24.6 � 0.4,

WKY þ RSV 22.2 � 0.4). RSV treat-

ment reduced left ventricular interstitial

collagen content in SHRs (SHR

19.6 � 1.0, SHR þ RSV 14.6 � 1.2*;

WKY 7.6 � 0.5 and WKY þ RSV

8.0 � 0.7% area), while perivascular

collagen content remained unchanged

(SHR: 33.9 � 1.4, SHR þ RSV

30.9 � 1.4; WKY 23.9 � 1.8 and

WKY þ RSV 24.7 � 1.3% area).

Statin treatment significantly lowered

mitral E/A flow in 19- and 20-month-

old SHRs (19 months: SHR 2.27 �0.11

and SHR þ RSV 1.82 � 0.08*; 20

months: SHR 2.65 � 0.36 and

SHR þ RSV 1.69 � 0.07*) as imaged

by echocardiography. Thus, in the

ageing SHR, RSV prevented increases

in cardiac stiffness, interstitial

collagen deposition, mitral E/A flow

and cardiac hypertrophy without

altering systolic blood pressure, aortic

media width and perivascular collagen

deposition, suggesting a role for RSV

in the attenuation of cardiovascular

remodelling during the development

of heart failure.

Rosuvastatin regulates migration of human vascular smoothmuscle cells via the RhoA and uPA/uPAR systems

Y. KIYAN,1 A. KUSCH2 AND I. DUMLER1

Hanover Medical School,1 Hanover, Charite-Franz-Volhard Clinic,2 Humboldt University at Berlin, Berlin, Germany

Migration and proliferation of vascular

smooth muscle cells (VSMC) play a

pivotal role in vascular remodelling. A

growing body of data from animal

models and human subjects suggest

that the serine protease urokinase

(uPA) and its specific receptor

(uPAR), are central to VSMC

migration and proliferation processes.

This study addresses possible

nonlipid-lowering effects of the 3-

hydroxy-3-methylglutaryl coenzyme A

reductase inhibitor, rosuvastatin, on

the uPA/uPAR-related functions of

human VSMC. Treatment of VSMC

with rosuvastatin significantly increased

expression of uPA and uPAR, as shown

by TaqMan analysis. Rosuvastatin

stimulated VSMC migration in the

modified Boyden chamber at concen-

tration ranges from 25 to 50 nM and

slightly inhibited VSMC migration at

micromolar concentrations whereas cell

proliferation remained arrested.

However, uPA-stimulated VSMC

migration was not affected by

rosuvastatin treatment. We assessed the

activation status of Rho proteins

required for the uPA-directed cell

migration using a pull-down assay.

Treatment of VSMC with rosuvastatin

led to increase of GTP-RhoA content

but had no effect on Rac1 or Cdc42

expression. In agreement with pull-

down assay data, we observed an

increased amount of RhoA associated

with the membrane fraction of VSMC

following rosuvastatin treatment.

Addition of uPA to rosuvastatin failed



to activate RhoA further. This supports

the data for cell migration and might be

a result of preactivation of VSMC

by endogenous uPA expressed in

response to rosuvastatin. To test the

effects of rosuvastatin on neointima

formation in the intact vessel wall,

isolated endothelial-cell denuded

porcine coronary arteries were used in

an ex vivo model of vascular

remodelling. The histological studies

confirmed an impact of rosuvastatin

on VSMC functional behaviour,

which might explain neointima

reduction in response to rosuvastatin.

Our data demonstrate that rosuva-

statin may exert its effects on vascular

remodelling by regulating the

fibrinolytic uPA/uPAR system in

VSMC. The underlying molecular

mechanism indicates the activation

of uPA/uPAR expression in response

to rosuvastatin that, in turn, leads to

up-regulation of GTP-RhoA, its

intracellular redistribution to cell

membranes and the stimulation of

VSMC migration.



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