Cell cycle and apoptosis genes in atherosclerosis Boesten, Lianne Simone Mirjam
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(2) &KDSWHU. 33$5DJDJRQLVPDQG DWKHURVFOHURVLV.
(3)
(4) 4HE DUAL 00!2DJ AGONIST TESAGLITAZAR REDUCES ATHEROSCLEROSIS DEVELOPMENT BEYOND ITS PLASMA CHOLESTEROL LOWERING EFFECTS IN !0/% ,EIDEN TRANSGENIC MICE ! 3USANNE - :ADELAAR
(5) ,IANNE 3- "OESTEN
(6) * 7OUTER *UKEMA "ART *- VAN 6LIJMEN 4EAKE +OOISTRA *EF * %MEIS %RIK ,UNDHOLM 'ERMAN #AMEJO ,OUIS - (AVEKES
(7)
(8) $EPARTMENT OF #ARDIOLOGY
(9) ,EIDEN 5NIVERSITY -EDICAL #ENTER 4./ 'AUBIUS ,ABORATORY
(10) "IOMEDICAL 2ESEARCH 5NIT $EPARTMENT OF 'ENERAL )NTERNAL -EDICINE
(11) ,EIDEN 5NIVERSITY -EDICAL #ENTER (EMOSTASIS AND 4HROMBOSIS 2ESEARCH #ENTER
(12) ,EIDEN 5NIVERSITY -EDICAL #ENTER
(13) ,EIDEN
(14) 4HE .ETHERLANDS !STRA :ENECA
(15) -ÚLNDAL
(16) 3WEDEN. $%675$&7 7E INVESTIGATED WHETHER THE DUAL 00!2DJ AGONIST TESAGLITAZAR HAS ANTI ATHEROGENIC EFFECTS IN !0/% ,EIDEN MICE WITH NORMAL AND REDUCED INSULIN SENSITIVITY !0/% ,EIDEN TRANSGENIC MICE WERE FED EITHER A LOW FAT ,& DIET OR A HIGH FAT (&
(17) INSULIN RESISTANCE INDUCING DIET )N BOTH ,& AND (& FED MICE
(18) ONE GROUP RECEIVED A HIGH CHOLESTEROL SUPPLEMENT WTWT (# GROUP ! SECOND GROUP RE CEIVED THE SAME (# SUPPLEMENT ALONG WITH TESAGLITAZAR MOLKG DIET 4 GROUP ! THIRD CONTROL GROUP RECEIVED A LOW CHOLESTEROL SUPPLEMENT WTWT ,# GROUP
(19) WHICH RESULTED IN PLASMA CHOLESTEROL LEVELS SIMILAR TO THOSE OF THE 4 GROUP )N BOTH (& AND ,& FED MICE
(20) TESAGLITAZAR DECREASED PLASMA CHOLESTEROL BY COM PARED WITH THE RESPECTIVE (# GROUPS CHOLESTEROL LEVELS WERE SIMILAR IN THE 4 AND ,# GROUPS )N ,& FED MICE
(21) TESAGLITAZAR REDUCED ATHEROSCLEROSIS IN THE AORTIC ROOT UP TO
(22) WHEREAS THE CHOLESTEROL MATCHED ,# GROUP HAD A REDUCTION OF )N (& FED MICE
(23) TESAGLITAZAR PRODUCED A REDUCTION IN ATHEROSCLEROSIS
(24) WHILE A REDUCTION WAS SEEN IN THE CHOLESTEROL MATCHED ,# GROUP &URTHERMORE
(25) TESAGLITAZAR TREATMENT SIGNIlCANTLY REDUCED LESION NUMBER BEYOND THAT EXPECTED FROM CHOLES TEROL LOWERING
(26) AND INDUCED A SHIFT TO LESS SEVERE LESIONS #ONCOMITANTLY
(27) TESAGLITAZAR REDUCED MACROPHAGE RICH AND COLLAGEN AREAS IN BOTH (& AND ,& FED MICE )N ADDI TION
(28) TESAGLITAZAR TREATMENT REDUCED INmAMMATORY MARKERS
(29) INCLUDING PLASMA SERUM AMYLOID ! LEVELS
(30) THE NUMBER OF ADHERING MONOCYTES
(31) AND NUCLEAR FACTOR N" ACTIVITY IN THE VESSEL WALL 4ESAGLITAZAR HAS ANTI ATHEROSCLEROTIC EFFECTS THAT GO BEYOND PLASMA CHOLESTEROL LOWERING 4HESE EFFECTS WERE MORE PRONOUNCED IN (& FED MICE 4ESAGLITAZAR MAY EX ERT THESE ACTIONS VIA ANTI INmAMMATORY EFFECTS.
(32) #HAPTER . !. . GONISTS OF THE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR 00!2 D HAVE POSITIVE EFFECTS ON LIPID METABOLISM BOTH IN ANIMAL MODELS AND IN CLINICAL PRACTICE !GONISTS OF 00!2 Jn THE THIAZOLIDINEDIONES ROSIGLITAZONE AND PIO GLITAZONE n IMPROVE INSULIN RESISTANCE IN TYPE DIABETES
(33) AND PIOGLITAZONE IMPROVES THE DYSLIPIDEMIA ASSOCIATED WITH INSULIN RESISTANCE )N ADDITION TO THESE EFFECTS
(34) BOTH 00!2D AND J AGONISTS HAVE ANTI INmAMMATORY PROPERTIES
(35)
(36) AND
(37) THEREFORE
(38) HAVE THE POTENTIAL TO PROVIDE ADDITIONAL CARDIOVASCULAR BENElT 00!2D AND J AGONISTS APPEAR TO ACT AT TWO DIFFERENT LEVELS TO COUNTERACT ATH EROSCLEROSIS 3YSTEMICALLY
(39) THEY AMELIORATE THE ATHEROGENIC LIPID PROlLE BY REDUCING PLASMA FREE FATTY ACIDS AND TRIGLYCERIDES
(40) AND INCREASING HIGH DENSITY LIPOPROTEIN ($, CHOLESTEROL LEVELS !T THE CELLULAR LEVEL
(41) 00!2 AGONISTS ACT ON MOST CELL TYPES INVOLVED IN ATHEROSCLEROSIS
(42) INCLUDING ENDOTHELIAL CELLS
(43) SMOOTH MUSCLE CELLS 3-#S
(44) MACROPHAGES AND LYMPHOCYTES
(45) REDUCING THEIR INVOLVEMENT IN THE TISSUE RESPONSE ASSOCIATED WITH PLAQUE DEVELOPMENT 4HESE AGONISTS DAMPEN THE SYSTEMIC RESPONSE TO INmAMMATION BY REDUCING LEVELS OF PLASMA PROTEINS SUCH AS # REACTIVE PROTEIN #20
(46) TUMOR NECROSIS FACTOR 4.& D AND INTERFERON )&. J INHIBITING INTERLEUKIN ), AND 4.&D SECRETION BY MONOCYTES AND REDUCING ), INDUCED SECRETION OF ), VIA NUCLEAR FACTOR .& N" SIGNALING PATHWAYS IN 3-#S
(47) 00!2 AGONISTS HAVE A NUMBER OF OTHER ACTIONS THAT POSITIVELY MODULATE VASCULAR EFFECTS )N THE ENDOTHELIUM
(48) FOR EXAMPLE
(49) THEY INHIBIT PRODUCTION OF THE VASOCON STRICTOR ENDOTHELIN
(50) AND INHIBIT CYTOKINE INDUCED EXPRESSION OF THE ADHESION MOLECULES INTERCELLULAR ADHESION MOLECULE AND VASCULAR CELL ADHESION MOLECULE )N MONOCYTEMACROPHAGES
(51) CHEMOTAXIS BY MONOCYTE CHEMOTACTIC PEPTIDE AND PROTEOLYTIC ENZYME ACTIVITY BY MATRIX METALLOPROTEINASE ARE INHIBITED
(52) AND THE PROLIFERATION AND MIGRATION OF 3-#S ARE INHIBITED "OTH 00!2D AND J STIMULATE !40 BINDING CASSETTE TRANSPORTER ! EXPRESSION
(53) THEREBY PROMOTING CHOLESTEROL EF mUX FROM MACROPHAGES AND POSSIBLY CHOLESTEROL EXCRETION INTO THE GUT )N THE CLINICAL SETTING
(54) 00!2D AGONISTS REDUCE CARDIOVASCULAR DISEASE #6$ RISK
(55) ESPECIALLY IN SUBJECTS WITH INSULIN RESISTANCE 00!2J AGONISTS HAVE BEEN TO SHOWN REDUCE THE PROGRESSION OF INTIMA MEDIA THICKENING IN PATIENTS WITH CORONARY ARTERY DISEASE
(56) AND RECENT EVIDENCE SUGGESTS THAT PIOGLITAZONE REDUCES THE INCIDENCE OF MYOCARDIAL INFARCTION AND STROKE IN PATIENTS WITH TYPE DIABETES AND PRE EXISTING #6$ $UAL 00!2DJ AGONISTS
(57) WHICH ARE AT AN EARLIER STAGE OF CLINICAL DEVELOPMENT
(58) HAVE BEEN SHOWN TO IMPROVE BOTH GLUCOSE AND LIPID ABNORMALITIES IN PATIENTS WITH INSULIN RESISTANCE AND TYPE DIABETES
(59) 4ESAGLITAZAR IS A DUAL 00!2DJ AGONIST THAT HAS DEMONSTRATED POSITIVE EFFECTS ON PLASMA GLUCOSE AND LIPID ABNORMALITIES IN ANIMAL MODELS OF TYPE DIABETES AND MET ABOLIC SYNDROME "ASED ON THEIR EFFECTS IN ANIMAL MODELS
(60) IT HAS BEEN PROPOSED THAT DUAL 00!2DJ AGONISTS MAY HAVE ADDITIONAL BENElTS
(61) BEYOND THEIR CHOLESTEROL LOWERING EFFECT
(62) IN REDUCING COMPONENTS OF INSULIN RESISTANCE THAT CONTRIBUTE TO ATHEROSCLEROSIS AND CARDIOVASCULAR DISEASE
(63) )N THIS STUDY
(64) WE EXAMINED WHETHER TESAGLITAZAR CAN CONFER ADDITIONAL CARDIOVASCULAR BENElT USING !0/% ,EIDEN TRANS GENIC MICE
(65) AN ESTABLISHED MODEL OF HUMAN HYPERLIPIDEMIA AND ATHEROSCLEROSIS 7HEN FED A HIGH CHOLESTEROL DIET
(66) !0/% ,EIDEN TRANSGENIC MICE DEVELOP A HUMAN LIKE LIPOPROTEIN PROlLE
(67) WHICH INCLUDES ELEVATED PLASMA LEVELS OF VERY LOW DENSITY LIPOPROTEIN 6,$,
(68) INTERMEDIATE DENSITY LIPOPROTEIN )$, AND LOW DENSI.
(69) . 00!2DJ AGONISM AND ATHEROSCLEROSIS . TY LIPOPROTEIN ,$, AND LEADS TO THE DEVELOPMENT OF ATHEROSCLEROSIS )N ADDITION
(70) WHEN FED A HIGH CALORIE
(71) HIGH FAT
(72) HIGH CHOLESTEROL DIET
(73) THESE MICE DEVELOP INSULIN RESISTANCE $EPENDING ON THEIR PLASMA CHOLESTEROL LEVELS
(74) !0/% ,EIDEN MICE DE VELOP ATHEROSCLEROTIC LESIONS THAT HAVE COMPARABLE MORPHOLOGICAL
(75) HISTOLOGICAL AND IMMUNOHISTOCHEMICAL CHARACTERISTICS TO HUMAN LESIONS 3INCE PLASMA CHOLESTER OL LEVELS IN !0/% ,EIDEN TRANSGENIC MICE CAN BE TITRATED TO ANY LEVEL BY ADJUSTING DIETARY CHOLESTEROL INTAKE
(76) WE WERE ABLE TO STUDY THE EFFECTS OF TESAGLITAZAR ON ATH EROGENESIS
(77) INDEPENDENT OF ITS TOTAL PLASMA CHOLESTEROL LOWERING EFFECT )N ADDITION
(78) WE WERE ABLE TO EXAMINE THESE EFFECTS UNDER BOTH NORMAL AND MILD INSULIN RESISTANT CONDITIONS 0(7+2'6 $QLPDOV &EMALE HETEROZYGOUS !0/% ,EIDEN TRANSGENIC MICE n MONTHS OF AGE
(79) CHARAC TERIZED BY AN %,)3! FOR HUMAN APO%
(80) WERE USED !NIMAL EXPERIMENTS WERE AP PROVED BY THE )NSTITUTIONAL !NIMAL #ARE AND 5SE #OMMITTEE OF 4HE .ETHERLANDS /RGANIZATION FOR !PPLIED 3CIENTIlC 2ESEARCH 4./ !NIMALS WERE PROVIDED BY 4./ "IOMEDICAL 2ESEARCH 'LHWV $URING A RUN IN PERIOD OF WEEKS
(81) ANIMALS RECEIVED EITHER A HIGH FATHIGH CHOLESTER OL (&(# DIET
(82) CONTAINING WTWT BOVINE LARD
(83) OR A LOW FATHIGH CHOLESTEROL ,&(# 7ESTERN TYPE DIET
(84) CONTAINING WTWT COCOA BUTTER !FTER THE RUN IN PERIOD
(85) THE (&(# MICE WERE MATCHED FOR AGE AND CHOLESTEROL LEVEL INTO GROUPS OF MICE EACH 4ABLE 4HE MICE MAINTAINED THE (& DIET IN AD DITION TO ONE OF THE FOLLOWING THREE TREATMENTS 4HE HIGH CHOLESTEROL (&(# GROUP RECEIVED A DIET CONTAINING WTWT CHOLESTEROL 4HE TESAGLITAZAR TREATED GROUP (&4 RECEIVED THE SAME DIET AS THE (# GROUP
(86) BUT THE DIET WAS SUPPLEMENTED WITH TESAGLITAZAR MOLKG DIET
(87) EQUALING GKG BODY WEIGHT PER DAY 4ESAGLITAZAR ;3 %THOXY ; ; METHYLSULPHONYLOXYPHENYL ETHOXY=PHENYL PROPANOIC ACID= WAS PROVIDED BY !STRA:ENECA 2$
(88) -ÚLNDAL
(89) 3WEDEN 4HE LOW CHOLESTEROL (&,# GROUP RECEIVED A DIET CONTAINING WTWT CHOLESTEROL TO TITRATE THE PLASMA CHOLESTEROL LEVEL TO THAT OF THE 4 GROUP
(90) AS DEDUCED FROM PREVIOUS EXPERIMENTS IN OUR LAB 4HE ,# GROUP SERVED AS THE CHOLESTEROL MATCHED CONTROL 4HE THREE GROUPS OF (& FED MICE WERE TREATED FOR WEEKS 4ABLE $IETS USED DURING THE STUDY $IET (IGH CHOLESTEROL WTWT. (IGH &AT ,OW &AT. (&(# ,&(#. 4REATMENT (IGH CHOLESTEROL AND TESAGLITAZAR WTWT MOLKG (&4 ,&4. $URATION -ATCHED LOW CHOLESTEROL WTWT (&,# ,&,#. WEEKS WEEKS.
(91) #HAPTER . !NIMALS THAT RECEIVED THE ,&(# DIET DURING THE RUN IN PERIOD WERE SIMILARLY RANDOMIZED INTO THREE GROUPS CONTAINING MICE )N ADDITION TO THEIR ,& DIET
(92) THE THREE GROUPS RECEIVED TREATMENT AS DESCRIBED ABOVE
(93) EXCEPT THAT TREATMENT LASTED WEEKS 4HUS
(94) THE THREE TREATMENT GROUPS WERE ,&(#
(95) ,&4 AND ,&,# !LL ANIMALS HAD FREE ACCESS TO FOOD AND WATER "ODY WEIGHT AND FOOD INTAKE WERE MONITORED THROUGHOUT THE STUDY. . $QDO\VLVRISODVPD !FTER A HOUR FAST
(96) COMMERCIALLY AVAILABLE KITS WERE USED TO MEASURE TOTAL PLASMA CHOLESTEROL .O 2OCHE $IAGNOSTICS AND TRIGLYCERIDE LEVELS .O " 3IG MA $IAGNOSTICS #HOLESTEROL EXPOSURE WAS CALCULATED AS THE AREA UNDER THE CURVE OF CHOLESTEROL LEVELS VERSUS TIME IN WEEKS ,IPOPROTEIN DISTRIBUTION WAS DETERMINED BY FAST PERFORMANCE LIQUID CHROMATOGRAPHIC &0,# SIZE FRACTIONATION 0HARMACIA 'LUCOSE AND INSULIN LEVELS WERE DETERMINED FOLLOWING SACRIlCE AT WEEK FOR (& FED ANIMALS AND WEEK FOR ,& FED ANIMALS 0LASMA GLUCOSE WAS MEASURED USING COMMERCIAL REAGENTS .O AND )NSTRUCHEMIE AND PLASMA INSULIN WAS MEASURED USING A MOUSE SPECIlC %,)3!
(97) !LPCO (OMEOSTASIS MODEL AS SESSMENT INSULIN RESISTANCE (/-! )2
(98) A SURROGATE MEASURE OF INSULIN RESISTANCE
(99) WAS CALCULATED AS THE PRODUCT OF FASTING INSULIN 5M, AND GLUCOSE MMOL, CONCENTRATIONS DIVIDED BY 0LASMA lBRINOGEN HOME MADE MOUSE KIT AND SERUM AMYLOID ! 3!! "IOSOURCE WERE MEASURED USING SPECIlC %,)3!S $QDO\VLVRIDWKHURVFOHURVLV !FTER WEEKS FOR (& FED MICE AND WEEKS FOR ,& FED MICE
(100) ANIMALS WERE SACRIlCED AND THE HEARTS WERE HARVESTED
(101) lXED AND EMBEDDED IN PARAFlN 3ERIAL M CROSS SECTIONS OF THE ENTIRE AORTIC VALVE AREA WERE PREPARED AND STAINED WITH HEMATOXYLIN PHLOXIN SAFFRON (03 FOR HISTOLOGICAL ANALYSIS
(102) AND WITH 3IRIUS 2ED TO QUANTIFY THE COLLAGEN AREA !THEROSCLEROTIC LESIONS WERE CATEGORIZED INTO TYPES )n6
(103) AS DESCRIBED PREVIOUSLY #ROSS SECTIONAL LESION AREAS WERE QUANTIlED USING ,EICA 1WIN MORPHOMETRIC SOFTWARE &OUR SECTIONS OF EACH SPECIMEN WERE ANALYZED AT M INTERVALS TO DETERMINE THE AVERAGE LESION NUMBER
(104) TYPE
(105) AND AREA )N ADDI TION
(106) DESCENDING AORTAS WERE ISOLATED AND SNAP FROZEN UNTIL FURTHER ANALYSIS $URING LATER ANALYSIS
(107) VESSELS WERE CLEANED OF ADHERENT FAT
(108) AND THEN STAINED FOR LIPIDS USING /IL RED / FOR hEN FACEv MORPHOMETRY OF THE ATHEROSCLEROTIC LESION AREA ,EICA 1WIN MORPHOMETRIC SOFTWARE !LL ANALYSES WERE PERFORMED BLIND
(109) WITHOUT PRIOR KNOWL EDGE OF FEEDING REGIME OR TREATMENT 4HE NUMBER OF MONOCYTES ADHERING TO ATHEROSCLEROTIC PLAQUES MAY GIVE AN INDICATION OF ENDOTHELIAL ACTIVATION
(110) AND THEREBY OF THE INmAMMATORY STATUS OF THE PLAQUE -ACROPHAGES WERE DETECTED USING !)! ANTISERUM
(111) !CCURATE #HEMICAL AND 3CIENTIlC 4HE INmAMMATORY STATUS OF PLAQUES WAS FURTHER EXAMINED BY ESTIMATING THE LOCAL PRESENCE OF .&N" A MAJOR REGULATORY COMPONENT OF INmAM MATORY REACTIONS IN THE PLAQUE .&N" WAS DETECTED USING MOUSE ANTI HUMAN P .&N" &
(112)
(113) 3ANTA #RUZ "IOTECHNOLOGY 4HE LEVEL OF .&N" POSITIVE STAINING WAS SCORED IN THE CYTOPLASM AND NUCLEUS FOR BOTH MACROPHAGES AND ENDOTHELIAL CELLS NO POSITIVITY
(114) TO POSITIVE CELLS
(115) ABOVE POSITIVE CELLS .
(116) . 00!2DJ AGONISM AND ATHEROSCLEROSIS . 6WDWLVWLFDODQDO\VLV .ON PARAMETRIC -ANN 7HITNEY 5 TESTS WERE USED TO ANALYZE TREATMENT DIFFERENCES
(117) UNLESS STATED OTHERWISE 0ROBABILITY VALUES OF 0 TWO SIDED WERE CONSIDERED SIGNIlCANT &REQUENCY DATA FOR LESION CATEGORIZATION WERE COMPARED USING THE &ISH ERS EXACT TEST !LL DATA ARE PRESENTED AS MEAN 3$ 5(68/76 3ODVPDOLSLGVDQGOLSRSURWHLQSUR¿OHV )N BOTH THE (& AND ,& FED MICE
(118) BODY WEIGHT &IGURE ! AND FOOD INTAKE DATA NOT SHOWN DID NOT DIFFER BETWEEN THE THREE TREATMENT GROUPS DURING THE STUDY PERIODS )N THE (& FED MICE
(119) PLASMA CHOLESTEROL LEVELS WERE LOWER IN THE TESAGLITAZAR TREATED GROUP THAN IN THE (&(# GROUP &IGURE " ! SIMILAR PATTERN WAS SEEN IN THE ,& FED MICE
(120) WITH PLASMA CHOLESTEROL LEVELS LOWER IN THE TESAGLITAZAR TREATED GROUP THAN IN THE ,&(# GROUP &IGURE " !S REQUIRED BY THE EXPERIMENTAL DESIGN 4ABLE
(121) THE TOTAL PLASMA CHOLESTEROL LEVELS WERE SIMILAR IN THE (&,# AND (&4 GROUPS AND IN THE ,&,# AND ,&4 GROUPS ,IPOPROTEIN PROlLES OF THE MICE SHOWED THAT TESAGLITAZAR DECREASED 6,$, CHO LESTEROL LEVELS IN BOTH (& AND ,& FED MICE DATA NOT SHOWN !DDITIONALLY
(122) FOLLOWING TESAGLITAZAR TREATMENT
(123) A LIPOPROTEIN FRACTION APPEARED WITH A SIZE BETWEEN ,$, AND ($, LIPOPROTEINS &IGURE # 7ESTERN BLOT ANALYSIS REVEALED THAT THIS LIPOPROTEIN FRACTION WAS POOR IN APO!) AND APO"
(124) BUT RICH IN APO% DATA NOT SHOWN !S DERIVED FROM THE AREA UNDER THE CURVE OF &IGURE "
(125) THE (&(# AND ,&(# GROUPS HAD SIGNIlCANTLY INCREASED EXPOSURE TO CHOLESTEROL COMPARED WITH THE RE SPECTIVE TESAGLITAZAR TREATED AND ,# GROUPS &IGURE $ 4HERE WAS NO SIGNIlCANT DIF FERENCE IN CHOLESTEROL EXPOSURE BETWEEN TESAGLITAZAR TREATED AND ,# CONTROL GROUPS 4RIGLYCERIDE LEVELS WERE SIGNIlCANTLY LOWER IN TESAGLITAZAR TREATED GROUPS COMPARED WITH (# GROUPS &IGURE % WITH BOTH (& AND ,& DIETS 0 0LASMA TESAGLITAZAR LEVELS REACHED NMOL, FOR THE (& GROUPS AND NMOL, FOR THE ,& GROUPS NS ,QVXOLQVHQVLWLYLW\ #HANGES IN GLUCOSE AND INSULIN LEVELS DURING THE STUDY ARE SHOWN IN 4ABLE )N (& FED MICE
(126) THE (/-! )2 INDEX INDICATED INSULIN RESISTANCE IN (&(# MICE AT WEEKS (/-! )2 WAS SIGNIlCANTLY LOWER IN BOTH THE (&4 AND (&,# GROUPS COM PARED WITH THE (&(# GROUP )N ,& FED MICE
(127) ONLY TESAGLITAZAR TREATMENT SIGNIlCANTLY REDUCED (/-! )2 COMPARED WITH BOTH ,&(# AND ,&,# MICE 0 $WKHURVFOHURVLV 4ESAGLITAZAR REDUCED ATHEROSCLEROSIS IN TREATED MICE COMPARED WITH THE RESPECTIVE (# GROUPS AND CHOLESTEROL MATCHED ,# GROUPS )N (& FED MICE
(128) hEN FACEv PREPARA TIONS OF THE DESCENDING AORTA SHOWED THAT LESION AREA WAS REDUCED BY IN THE TESAGLITAZAR TREATED GROUP COMPARED WITH THE (&(# GROUP
(129) AND BY COMPARED WITH THE CHOLESTEROL MATCHED (&,# CONTROL GROUP &IGURE ! 4HESE CHANGES DID NOT REACH STATISTICAL SIGNIlCANCE )N THE ,& FED MICE
(130) LESION AREA WAS SIGNIlCANTLY .
(131) 4ABLE (/-! )2 CALCULATIONS AS A MEASURE FOR INSULIN RESISTANCE IN HIGH FAT AND LOW FAT FED MICE $IET. 4REATMENT. 7EEKS. 'LUCOSE MMOL,. )NSULIN G,. (/-! )2. . . . . . . (# 4 . ,# (/-! )2 )NSULIN 5M, X 'LUCOSE MMOL, . 3IGNIlCANTLY DIFFERENT FROM (#
(132) 0 (# HIGH CHOLESTEROL 4 TESAGLITAZAR ,# LOW CHOLESTEROL. . . . (IGH FAT (# 4 ,#. . #HAPTER . ,OW FAT. . REDUCED BY 0 IN THE TESAGLITAZAR TREATED GROUP COMPARED WITH THE ,& (# GROUP
(133) AND BY NS COMPARED WITH THE CHOLESTEROL MATCHED ,&,# GROUP &IGURE " #ONSISTENT WITH THE DESCENDING AORTA DATA
(134) CROSS SECTIONS OF THE AORTIC VALVE AREA SHOWED THAT TESAGLITAZAR REDUCED ATHEROSCLEROSIS &IGURE " )N (& FED MICE
(135) TREATMENT WITH TESAGLITAZAR SIGNIlCANTLY REDUCED TOTAL LESION AREA BY COMPARED WITH THE (&(# GROUP
(136) AND BY COMPARED TO THE CHOLESTEROL MATCHED (&,# CONTROL GROUP 0 )N THE ,& FED MICE
(137) TESAGLITAZAR TREATMENT RESULTED IN A SIG NIlCANT REDUCTION IN TOTAL LESION AREA COMPARED WITH THE ,&(# GROUP AND A NON SIGNIlCANT REDUCTION IN TOTAL LESION AREA COMPARED WITH THE CHOLESTEROL MATCHED ,&,# CONTROL GROUP )N THE SAME CROSS SECTIONS
(138) THE AVERAGE NUMBER OF LESIONS PER ANIMAL DID NOT DIFFER SIGNIlCANTLY BETWEEN THE (# AND ,# CONTROL GROUPS IN (& FED MICE &IGURE # (OWEVER
(139) TREATMENT WITH TESAGLITAZAR SIGNIlCANTLY REDUCED THE AVERAGE NUMBER OF LESIONS BY COMPARED WITH THE (&(# GROUP AND BY COMPARED WITH THE CHOLESTEROL MATCHED (&,# GROUP 0 4REATMENT WITH TESAGLITAZAR DID NOT AF FECT THE AVERAGE NUMBER OF LESIONS IN ,& FED MICE &IGURE # 7HEN LESIONS WERE CATEGORIZED AS EITHER MILD OR SEVERE IN (& FED MICE
(140) THERE WAS A SIGNIlCANT SHIFT 0 FROM SEVERE TO MILD LESIONS IN TESAGLITAZAR TREATED ANIMALS &IGURE $ !L THOUGH THERE WAS A SIMILAR TREND SEEN IN ,& FED MICE &IGURE $
(141) THERE WAS NO DIFFERENCE IN MILD AND SEVERE LESION CATEGORIZATION BETWEEN THE ,&4 AND ,&,# GROUPS 4O FURTHER CHARACTERIZE THE ATHEROSCLEROTIC LESIONS
(142) WE MEASURED MACROPHAGE AND COLLAGEN AREAS IN CROSS SECTIONS SERIAL TO THOSE USED FOR MORPHOMETRY &IGURE )N (& FED MICE
(143) THE MACROPHAGE POSITIVE AREA WAS LARGER IN THE (# GROUP COM PARED WITH THE TESAGLITAZAR AND ,# GROUPS &IGURE !
(144) # -OREOVER
(145) THE MACROPHAGE POSITIVE AREA WAS SMALLER IN THE TESAGLITAZAR GROUP THAN IN THE CHOLESTEROL MATCHED ,# GROUP 4HE COLLAGEN POSITIVE AREAS FOLLOWED A SIMILAR TREND &IGURE !
(146) # 3INCE THE TOTAL CROSS SECTIONAL LESION AREA WAS LARGER IN ,& FED MICE THAN IN (& FED MICE
(147) MACROPHAGE AND COLLAGEN AREAS WERE ALSO LARGER AND THE ABSOLUTE AREAS FOLLOWED THE LESION AREA TREND DATA NOT SHOWN 7HEN EXPRESSED AS A PERCENTAGE OF THE TOTAL .
(148) . )/,&23&1/,- . . /%86&*()3 (. . . . .
(149).
(150). . . . . *-&!&&+2. . .
(151) .
(152) . . . .
(153) *-&!&&+2. 1*(,8$&1*%&2- .
(154). . . . . 99 9. 9 9. . . 9 9 9.
(155) *-&!&&+2. . . . . 1"$3*/. . . . . . .
(156). . . . . *-&!&&+2.
(157) . . . . . . . . . . . . )/,&23&1/,- . )/,&23&1/,&70/ 241&- 6&&+2. .
(158) . . 1"$3*/.. . *-&!&&+2. . .
(159)
(160) . . . . . . . . 00!2DJ AGONISM AND ATHEROSCLEROSIS . . . . 9 9. 9 9. 9. . *-&!&&+2. 9 . &IGURE %FFECT OF TESAGLITAZAR ON PLASMA LIPIDS IN !0/% ,EIDEN MICE WITH LEFT PANELS AND WITHOUT RIGHT PANELS INSULIN RESISTANCE ! BODY WEIGHT OVER TIME " PLASMA CHOLESTEROL OVER TIME # LIPOPROTEIN PROlLES $ TOTAL CHOLESTEROL EXPOSURE % PLASMA TRIGLYCERIDES OVER TIME 4O INCREASE PLASMA CHOLESTEROL LEVELS AT WEEKS
(161) THE (&,# DIETARY CHOLESTEROL WAS INCREASED FROM TO CHOLESTEROL WTWT 0LASMA CHOLESTEROL LEVELS IN THE (&,# GROUP RETURNED TO LEVELS COMPARABLE TO THE 4 GROUP BY WEEKS #IRCLES (&(# OR ,&(# TRIANGLES (&4 OR ,&4 SQUARES (&,# OR ,&,# 0 .
(162) .'"$&,&2*/."1&". . .
(163). . . 1/222&$3*/.",,&2*/. "1&"- . . 5&1"(&.4-#&1 /',&2*/.2. #HAPTER . /'3/3",.4-#&1 /',&2*/.2. .
(164). . . . . .
(165) . . . . . .
(166) . .
(167) . . . . . . . . .
(168) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(169) . . . . . . -*,%. 2&5&1&. -*,%. 2&5&1&. &IGURE %FFECT OF TESAGLITAZAR ON ATHEROSCLEROSIS IN THE AORTA OF !0/% ,EIDEN MICE WITH LEFT AND WITHOUT RIGHT INSULIN RESISTANCE 3HOWN ARE ! THE AORTIC hEN FACEv ATHEROSCLEROTIC LESION AREA " THE CROSS SECTIONAL LESION AREA IN THE AORTIC VALVE AREA # TOTAL NUMBER OF LESIONS AND $ LESION SEVERITY 0 .
(170) . 00!2DJ AGONISM AND ATHEROSCLEROSIS . /,,"(&. *1*42 &%. "$1/0)"(&
(171) . . . "$1/0)"(&"1&" - . .
(172) . /,,"(&."1&" - . . . . . . . . . . . .
(173) . . . .
(174) .
(175) . . . . . . . . . . . . . . . . &IGURE #ROSS SECTIONAL LESION CHARACTERISTICS ! 2EPRESENTATIVE MICROSCOPIC IMAGES OF MACROPHAGE AND COLLAGEN STAINING OF (& FED MICE " MACROPHAGE AREA # COLLAGEN AREA . 0 . LESION AREA
(176) COLLAGEN DECREASED AND MACROPHAGES INCREASED IN ACCORDANCE WITH THE SHIFT TO LESS SEVERE LESIONS ,QÀDPPDWRU\PDUNHUV 3!! LEVELS WERE SIGNIlCANTLY REDUCED 0 IN TESAGLITAZAR TREATED GROUPS COM PARED WITH (# GROUPS IN BOTH (& FED AND ,& FED MICE &IGURE ! )N (& FED MICE
(177) TESAGLITAZAR TREATMENT REDUCED 3!! LEVELS FURTHER THAN ,# TREATMENT .
(178) ,&5&,2(-,. . . . . . . 4-#&1/'"%)&1*.( -/./$83&22&$3*/.. #HAPTER . . . . .
(179). . . . .
(180) . . . . . . . . . . . . . . . &IGURE %FFECT OF TESAGLITAZAR ON INmAMMATORY PARAMETERS IN !0/% ,EIDEN MICE WITH LEFT OR WITHOUT RIGHT INSULIN RESISTANCE ! PLASMA 3!! LEVEL " MONOCYTE ADHERENCE 0 . &IBRINOGEN LEVELS WERE UNAFFECTED DATA NOT SHOWN )N BOTH (& FED AND ,& FED MICE THERE WERE FEWER ADHERING MONOCYTES IN TESAGLITAZAR TREATED GROUPS COMPARED WITH (# GROUPS &IGURE " 4HERE WERE NO DIFFERENCES BETWEEN THE TESA GLITAZAR TREATED GROUPS AND THE CHOLESTEROL MATCHED ,# CONTROL GROUPS 0 .&N" STAINING WAS FOUND IN THE CYTOSOL AND NUCLEI OF BOTH ENDOTHELIAL CELLS AND MACROPHAGES &IGURE ! 3-#S REMAINED UNSTAINED 0OSITIVELY STAINED ENDO THELIAL CELLS WERE OBSERVED ON PLAQUES 7HEN OBSERVED ON NORMAL VESSEL WALLS
(181) THE POSITIVELY STAINED CELLS WERE IN CLOSE PROXIMITY TO THE SHOULDER REGIONS OF PLAQUES )N BOTH (& FED AND ,& FED MICE
(182) 0 .&N" EXPRESSION &IGURE "
(183) # FOLLOWED THE SAME PATTERN AS TOTAL LESION NUMBERS &IGURE # ',6&866,21 4HIS STUDY SHOWED THAT TESAGLITAZAR HAS ATHEROSCLEROSIS REDUCING CAPACITIES IN !0/% ,EIDEN TRANSGENIC MICE THAT CANNOT BE ATTRIBUTED SOLELY TO ITS REDUCTION OF PLASMA TOTAL CHOLESTEROL 4HIS ANTI ATHEROSCLEROTIC EFFECT WAS MORE NOTABLE WHEN THE ANIMALS WERE PLACED ON A DIET THAT GENERATED INSULIN RESISTANCE
(184) OBESITY AND MOD ERATE HYPERTRIGLYCERIDEMIA
(185) CONDITIONS THAT CONTRIBUTE TO METABOLIC SYNDROME IN .
(186) . 00!2DJ AGONISM AND ATHEROSCLEROSIS . . .%/3)&,*", 0/2*3*5*38. . . . . . . . "$1/0)"(& 0/2*3*5*38. . . . . . . . . . . . . . . . . . . &IGURE %FFECT OF TESAGLITAZAR ON THE INmAMMATORY MARKER .&N" IN ATHEROSCLEROTIC PLAQUES OF !0/% ,EIDEN MICE WITH LEFT OR WITHOUT RIGHT INSULIN RESISTANCE ! 2EPRESENTATIVE MICROSCOPIC PICTURES OF P .&N" POSITIVE STAINING OF ATHEROSCLEROTIC PLAQUES SCALE BAR M " 3CORING OF ENDOTHELIAL .&N" POSITIVITY IN THE CYTOSOL BLACK BARS AND NUCLEUS WHITE BARS # 3CORING OF MACROPHAGE .&N" POSITIVITY IN THE CYTOSOL BLACK BARS AND NUCLEUS WHITE BARS 0 . HUMANS 4HE MECHANISM BY WHICH TESAGLITAZAR REDUCED ATHEROGENESIS IN THESE MICE INVOLVED DIRECT ACTIONS ON THE PRO INmAMMATORY TISSUE RESPONSE OF VASCULAR CELLS 4HE HYPERLIPIDEMIC !0/% ,EIDEN MICE USED HERE HAVE A LIPOPROTEIN PROlLE THAT IS MORE SIMILAR TO THE HUMAN PROlLE THAN THOSE OF EITHER APO% OR ,$,R MICE )N AGREEMENT WITH PREVIOUS STUDIES WITH !0/% ,EIDEN MICE
(187)
(188) WE WERE ABLE TO TITRATE PLASMA CHOLESTEROL LEVELS BY ADJUSTING DIETARY CHOLESTEROL INTAKE 0REVIOUS STUDIES HAVE ALSO SHOWN THAT THESE MICE RESPOND TO HYPOLIPIDEMIC DRUGS TREATMENT WITH STATINS REDUCES PLASMA CHOLESTEROL
(189) AND TREATMENT WITH A 00!2D AGONIST RE DUCES BOTH PLASMA CHOLESTEROL AND TRIGLYCERIDE LEVELS UNPUBLISHED DATA )N ADDI.
(190) #HAPTER . TION
(191) WE SHOWED IN AN EARLIER DOSE lNDING STUDY THAT !0/% ,EIDEN MICE RESPOND TO THE DUAL 00!2DJ AGONIST TESAGLITAZAR )N THE PRESENT STUDY
(192) WE AIMED FOR MILD CHOLESTEROL LOWERING WITH TESAGLITAZAR
(193) IN ORDER TO INVESTIGATE DIRECT ANTI ATHEROSCLE ROTIC EFFECTS ON THE VASCULAR WALL !T A DOSE OF TESAGLITAZAR MOLKG DIET OR GKG BODY WEIGHTDAY
(194) A MILD DECREASE IN PLASMA CHOLESTEROL OF APPROXIMATELY WAS ACHIEVED 4HE LIPOPROTEIN PROlLES OF THE MICE SUGGESTED THAT TREATMENT WITH TESAGLITAZAR RESULTED IN THE FORMATION OF AN ADDITIONAL PARTICLE
(195) SIZED BETWEEN THE ,$, AND ($, FRACTIONS 7ESTERN BLOTTING CHARACTERIZED THE PARTICLE AS POOR IN APO!) AND APO"
(196) BUT RICH IN APO% DATA NOT SHOWN 3IMILAR LIPOPROTEIN PROlLES HAVE BEEN OBSERVED FOLLOWING TREATMENT OF !0/% ,EIDEN MICE WITH THE 00!2D AGONIST FENOlBRATE UNPUBLISHED DATA 3INCE CHOLESTERYL ESTER TRANSFER PROTEIN IS NOT EXPRESSED IN MICE
(197) THESE PARTICLES COULD REPRESENT LARGE APO% RICH ($, &URTHERMORE
(198) THE APPEARANCE OF THESE LARGE APO% RICH PARTICLES DURING TESAGLITAZAR TREATMENT WAS ASSOCIATED WITH A DECREASE IN ATHEROSCLEROSIS
(199) SUGGESTING THAT THEY MAY HAVE FAVORABLE ANTI ATHERO SCLEROTIC PROPERTIES (OWEVER
(200) IT REMAINS UNCLEAR WHETHER THE ACCUMULATION OF THESE PARTICLES IS CLINICALLY RELEVANT
(201) OR A MOUSE SPECIlC EFFECT 4O EXAMINE THE PLEIOTROPIC EFFECTS OF TESAGLITAZAR THAT MIGHT CONTRIBUTE TO A REDUCTION IN ATHEROSCLEROSIS BEYOND THAT PROVIDED BY LIPOPROTEIN CHANGES
(202) WE ANA LYZED THE LEVELS OF ANTI INmAMMATORY MARKERS 3!! AND lBRINOGEN IN PLASMA
(203) AND EXAMINED ADHERING MONOCYTES AND VASCULAR .&N" EXPRESSION IN ATHEROSCLEROTIC PLAQUES 7E FOUND A DECREASE IN PLASMA 3!! LEVELS FOR TESAGLITAZAR TREATED MICE
(204) BUT NO CHANGE IN PLASMA lBRINOGEN LEVELS )N TESAGLITAZAR TREATED MICE
(205) FEWER MONOCYTES ADHERED TO THE ENDOTHELIUM OVER PLAQUES
(206) COINCIDING WITH DECREASED .&N" EXPRES SION AT THE SAME LOCATION 0REVIOUS STUDIES HAVE SHOWN EVIDENCE FOR ANTI INmAMMA TORY ACTIVITIES OF 00!2 D AND J AGONISTS
(207) DUE TO UPREGULATION OF )N"
(208) LEADING TO DE CREASED .&N"# %"0E COMPLEXES AND SUPPRESSION OF # REACTIVE PROTEIN SYNTHESIS /UR MODEL PROVIDES FURTHER EVIDENCE OF THE ANTI INmAMMATORY EFFECTS OF TESAGLITAZAR
(209) INCLUDING REDUCED TOTAL LESION AREA AS A RESULT OF DECREASED RELATIVE MACROPHAGE AND COLLAGEN AREAS "OTH EFFECTS CONTRIBUTED TO THE OBSERVED DECREASE IN PLAQUE SEVERITY IN DRUG TREATED ANIMALS 4HESE ANTI INmAMMATORY EFFECTS WERE MORE PRONOUNCED IN THE TESAGLITAZAR GROUPS THAN IN THE ,# GROUPS
(210) AND WERE THUS NOT DUE TO CHOLESTEROL LOWERING PER SE !LTHOUGH THE ANTI INmAMMATORY EFFECT OF TESAGLITAZAR WAS OBSERVED IN BOTH (& AND ,& FED MICE
(211) THE EFFECT OF TESAGLITAZAR WAS GREATER UNDER (& FED CONDITIONS 4HIS MIGHT BE ASCRIBED TO DIFFERENCES IN THE LEVEL OF INSULIN RESISTANCE BETWEEN THE TWO GROUPS (OWEVER
(212) WE CANNOT EXCLUDE THE POSSIBILITY THAT THE DIFFERENCE MIGHT BE DUE TO THE RELATIVE LENGTH OF THE TREATMENT PERIODS VS WEEKS
(213) OR TO A DIFFER ENCE IN PLASMA CHOLESTEROL LEVELS )N SUMMARY
(214) THE DUAL 00!2DJAGONIST TESAGLITAZAR SHOWED SIGNIlCANT ANTI ATH EROGENIC EFFECTS IN THIS MOUSE MODEL
(215) ESPECIALLY IN ANIMALS WITH MODERATE INSULIN RESISTANCE 4HESE POSITIVE RESULTS DID NOT SOLELY RESULT FROM TESAGLITAZAR INDUCED RE DUCTIONS IN TOTAL CHOLESTEROL LEVELS )N ADDITION TO THE BENElCIAL EFFECTS ON LIPID AND GLUCOSE ABNORMALITIES PREVIOUSLY SHOWN IN ANIMAL MODELS OF TYPE DIABETES AND THE METABOLIC SYNDROME
(216) TESAGLITAZAR ALSO DEMONSTRATED ANTI INmAMMATORY AND ANTI ATHEROSCLEROTIC EFFECTS IN THE VASCULAR WALL 4HE RESULTS FROM THIS STUDY SHOW THAT .
(217) . 00!2DJ AGONISM AND ATHEROSCLEROSIS . THE BENElCIAL EFFECTS OF TESAGLITAZAR ON ATHEROSCLEROSIS INVOLVE A NUMBER OF DIFFERENT PATHWAYS $&.12:/('*(0(176 4HIS STUDY WAS SUPPORTED BY THE .ETHERLANDS /RGANIZATION OF 3CIENTIlC 2ESEARCH .7/:ON-W GRANT NO
(218) THE .ETHERLANDS (EART &OUNDATION GRANT NO AND !STRA:ENECA
(219) -ÚLNDAL
(220) 3WEDEN *7* IS A CLINICAL ESTABLISHED INVESTI GATOR OF THE .ETHERLANDS (EART &OUNDATION $ 7E THANK THE TECHNICIANS OF 4./ "IOMEDICAL 2ESEARCH AND !STRA:ENECA 3WEDEN FOR THEIR EXCELLENT TECHNICAL ASSISTANCE 5()(5(1&(6 &RICK -(
(221) %LO /
(222) (AAPA +
(223) (EINONEN /0
(224) (EINSALMI 0
(225) (ELO 0
(226) (UTTUNEN *+
(227) +AITANIEMI 0
(228) +OSKINEN 0
(229) -ANNINEN 6
(230) (ELSINKI (EART 3TUDY PRIMARY PREVENTION TRIAL WITH GEMlBROZIL IN MIDDLE AGED MEN WITH DYSLIPIDEMIA 3AFETY OF TREATMENT
(231) CHANGES IN RISK FACTORS
(232) AND INCIDENCE OF CORONARY HEART DISEASE . %NGL * -ED 2UBINS ("
(233) 2OBINS 3*
(234) #OLLINS $
(235) &YE #,
(236) !NDERSON *7
(237) %LAM -"
(238) &AAS &(
(239) ,INARES %
(240) 3CHAEFER %*
(241) 3CHECTMAN '
(242) 7ILT 4*
(243) 7ITTES * 'EMlBROZIL FOR THE SECONDARY PREVENTION OF CORONARY HEART DISEASE IN MEN WITH LOW LEVELS OF HIGH DENSITY LIPOPROTEIN CHOLESTEROL 6ETERANS !FFAIRS (IGH $ENSITY ,IPOPROTEIN #HOLESTEROL )NTERVENTION 4RIAL 3TUDY 'ROUP . %NGL * -ED 4AILLEUX !
(244) 4ORPIER '
(245) -EZDOUR (
(246) &RUCHART *#
(247) 3TAELS "
(248) &IEVET # -URINE MODELS TO INVESTIGATE PHARMACOLOGICAL COMPOUNDS ACTING AS LIGANDS OF 00!2S IN DYSLIPIDEMIA AND ATHEROSCLEROSIS 4RENDS 0HARMACOL 3CI ,EBOVITZ (%
(249) $OLE *&
(250) 0ATWARDHAN 2
(251) 2APPAPORT %"
(252) &REED -) 2OSIGLITAZONE MONOTHERAPY IS EFFECTIVE IN PATIENTS WITH TYPE DIABETES * #LIN %NDOCRINOL -ETAB 2OSENBLATT 3
(253) -ISKIN "
(254) 'LAZER ."
(255) 0RINCE -*
(256) 2OBERTSON +% 4HE IMPACT OF PIOGLITAZONE ON GLYCEMIC CONTROL AND ATHEROGENIC DYSLIPIDEMIA IN PATIENTS WITH TYPE DIABETES MELLITUS #ORON !RTERY $IS 7INKLER +
(257) +ONRAD 4
(258) &ULLERT 3
(259) &RIEDRICH )
(260) $ESTANI 2
(261) "AUMSTARK -7
(262) +REBS +
(263) 7IELAND (
(264) -ARZ 7 0IOGLITAZONE REDUCES ATHEROGENIC DENSE ,$, PARTICLES IN NONDIABETIC PATIENTS WITH ARTERIAL HYPERTENSION A DOUBLE BLIND
(265) PLACEBO CONTROLLED STUDY $IABETES #ARE 8U *
(266) 3TORER 0$
(267) #HAVIS *!
(268) 2ACKE -+
(269) $REW 0$ !GONISTS FOR THE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AND THE RETINOID 8 RECEPTOR INHIBIT INmAMMATORY RESPONSES OF MICROGLIA * .EUROSCI 2ES :INGARELLI "
(270) #OOK *! 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA IS A NEW THERAPEUTIC TARGET IN SEPSIS AND INmAMMATION 3HOCK (ANSSON '+ )NmAMMATION
(271) ATHEROSCLEROSIS
(272) AND CORONARY ARTERY DISEASE . %NGL * -ED $UEZ (
(273) &RUCHART *#
(274) 3TAELS " 00!23 IN INmAMMATION
(275) ATHEROSCLEROSIS AND THROMBOSIS * #ARDIOVASC 2ISK *IANG #
(276) 4ING !4
(277) 3EED " 00!2 GAMMA AGONISTS INHIBIT PRODUCTION OF MONOCYTE INmAMMATORY CYTOKINES .ATURE -ARX .
(278) $UEZ (
(279) &RUCHART *#
(280) 3TAELS " 0EROXISOME PROLIFERATOR ACTIVATED RECEPTORS AND ATHEROGENESIS REGULATORS OF GENE EXPRESSION IN VASCULAR CELLS #IRC 2ES $ELERIVE 0
(281) $E "OSSCHER +
(282) "ESNARD 3
(283) 6ANDEN "ERGHE 7
(284) 0ETERS *-
(285) 'ONZALEZ &*
(286) &RUCHART *#
(287) 4EDGUI !
(288) (AEGEMAN '
(289) 3TAELS " 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA .
(290) . . . #HAPTER . . . . . . . . NEGATIVELY REGULATES THE VASCULAR INmAMMATORY GENE RESPONSE BY NEGATIVE CROSS TALK WITH TRANSCRIPTION FACTORS .& KAPPA" AND !0 * "IOL #HEM 0OYNTER -%
(291) $AYNES 2! 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA ACTIVATION MODULATES CELLULAR REDOX STATUS
(292) REPRESSES NUCLEAR FACTOR KAPPA" SIGNALING
(293) AND REDUCES INmAMMATORY CYTOKINE PRODUCTION IN AGING * "IOL #HEM $ELERIVE 0
(294) -ARTIN .IZARD &
(295) #HINETTI '
(296) 4ROTTEIN &
(297) &RUCHART *#
(298) .AJIB *
(299) $URIEZ 0
(300) 3TAELS " 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR ACTIVATORS INHIBIT THROMBIN INDUCED ENDOTHELIN PRODUCTION IN HUMAN VASCULAR ENDOTHELIAL CELLS BY INHIBITING THE ACTIVATOR PROTEIN SIGNALING PATHWAY #IRC 2ES -ARTIN .IZARD &
(301) &URMAN #
(302) $ELERIVE 0
(303) +ANDOUSSI !
(304) &RUCHART *#
(305) 3TAELS "
(306) $URIEZ 0 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR ACTIVATORS INHIBIT OXIDIZED LOW DENSITY LIPOPROTEIN INDUCED ENDOTHELIN SECRETION IN ENDOTHELIAL CELLS * #ARDIOVASC 0HARMACOL 0ASCERI 6
(307) 7U ($
(308) 7ILLERSON *4
(309) 9EH %4 -ODULATION OF VASCULAR INmAMMATION IN VITRO AND IN VIVO BY PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA ACTIVATORS #IRCULATION *ACKSON 3-
(310) 0ARHAMI &
(311) 8I 80
(312) "ERLINER *!
(313) (SUEH 7!
(314) ,AW 2%
(315) $EMER ,, 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR ACTIVATORS TARGET HUMAN ENDOTHELIAL CELLS TO INHIBIT LEUKOCYTE ENDOTHELIAL CELL INTERACTION !RTERIOSCLER 4HROMB 6ASC "IOL ,EE (
(316) 3HI 7
(317) 4ONTONOZ 0
(318) 7ANG 3
(319) 3UBBANAGOUNDER '
(320) (EDRICK ##
(321) (AMA 3
(322) "ORROMEO #
(323) %VANS 2-
(324) "ERLINER *!
(325) .AGY , 2OLE FOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA IN OXIDIZED PHOSPHOLIPID INDUCED SYNTHESIS OF MONOCYTE CHEMOTACTIC PROTEIN AND INTERLEUKIN BY ENDOTHELIAL CELLS #IRC 2ES 3HU (
(326) 7ONG "
(327) :HOU '
(328) ,I 9
(329) "ERGER *
(330) 7OODS *7
(331) 7RIGHT 3$
(332) #AI 41 !CTIVATION OF 00!2ALPHA OR GAMMA REDUCES SECRETION OF MATRIX METALLOPROTEINASE BUT NOT INTERLEUKIN FROM HUMAN MONOCYTIC 4(0 CELLS "IOCHEM "IOPHYS 2ES #OMMUN 'OETZE 3
(333) 8I 80
(334) +AWANO (
(335) 'OTLIBOWSKI 4
(336) &LECK %
(337) (SUEH 7!
(338) ,AW 2% 00!2 GAMMA LIGANDS INHIBIT MIGRATION MEDIATED BY MULTIPLE CHEMOATTRACTANTS IN VASCULAR SMOOTH MUSCLE CELLS * #ARDIOVASC 0HARMACOL #HINETTI '
(339) ,ESTAVEL 3
(340) "OCHER 6
(341) 2EMALEY !4
(342) .EVE "
(343) 4ORRA )0
(344) 4EISSIER %
(345) -INNICH !
(346) *AYE -
(347) $UVERGER .
(348) "REWER ("
(349) &RUCHART *#
(350) #LAVEY 6
(351) 3TAELS " 00!2 ALPHA AND 00!2 GAMMA ACTIVATORS INDUCE CHOLESTEROL REMOVAL FROM HUMAN MACROPHAGE FOAM CELLS THROUGH STIMULATION OF THE !"#! PATHWAY .AT -ED &AZIO 3
(352) ,INTON -& 4HE ROLE OF lBRATES IN MANAGING HYPERLIPIDEMIA MECHANISMS OF ACTION AND CLINICAL EFlCACY #URR !THEROSCLER 2EP 3IDHU *3
(353) +APOSZTA :
(354) -ARKUS (3
(355) +ASKI *# %FFECT OF ROSIGLITAZONE ON COMMON CAROTID INTIMA MEDIA THICKNESS PROGRESSION IN CORONARY ARTERY DISEASE PATIENTS WITHOUT DIABETES MELLITUS !RTERIOSCLER 4HROMB 6ASC "IOL $ORMANDY *!
(356) #HARBONNEL "
(357) %CKLAND $*
(358) %RDMANN %
(359) -ASSI "ENEDETTI -
(360) -OULES )+
(361) 3KENE !-
(362) 4AN -(
(363) ,EFEBVRE 0*
(364) -URRAY '$
(365) 3TANDL %
(366) 7ILCOX 2'
(367) 7ILHELMSEN ,
(368) "ETTERIDGE *
(369) "IRKELAND +
(370) 'OLAY !
(371) (EINE 2*
(372) +ORANYI ,
(373) ,AAKSO -
(374) -OKAN -
(375) .ORKUS !
(376) 0IRAGS 6
(377) 0ODAR 4
(378) 3CHEEN !
(379) 3CHERBAUM 7
(380) 3CHERNTHANER '
(381) 3CHMITZ /
(382) 3KRHA *
(383) 3MITH 5
(384) 4ATON * 3ECONDARY PREVENTION OF MACROVASCULAR EVENTS IN PATIENTS WITH TYPE DIABETES IN THE 02/ACTIVE 3TUDY 02/SPECTIVE PIOGLIT!ZONE #LINICAL 4RIAL )N MACRO6ASCULAR %VENTS A RANDOMISED CONTROLLED TRIAL ,ANCET &AGERBERG "
(385) %DWARDS 3
(386) (ALMOS 4
(387) ,OPATYNSKI *
(388) 3CHUSTER (
(389) 3TENDER 3
(390) 3TOA "IRKETVEDT '
(391) 4ONSTAD 3
(392) (ALLDORSDOTTIR 3
(393) 'AUSE .ILSSON ) 4ESAGLITAZAR
(394) A NOVEL DUAL PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHAGAMMA AGONIST
(395) DOSE DEPENDENTLY IMPROVES THE METABOLIC ABNORMALITIES ASSOCIATED WITH INSULIN RESISTANCE IN A NON DIABETIC POPULATION $IABETOLOGIA 3AAD -&
(396) 'RECO 3
(397) /SEI +
(398) ,EWIN !*
(399) %DWARDS #
(400) .UNEZ -
(401) 2EINHARDT 22 2AGAGLITAZAR IMPROVES GLYCEMIC CONTROL AND LIPID PROlLE IN TYPE DIABETIC SUBJECTS A WEEK
(402) DOUBLE BLIND
(403) PLACEBO CONTROLLED DOSE RANGING STUDY WITH AN OPEN PIOGLITAZONE ARM .
(404) . 00!2DJ AGONISM AND ATHEROSCLEROSIS . $IABETES #ARE ,JUNG "
(405) "AMBERG +
(406) $AHLLOF "
(407) +JELLSTEDT !
(408) /AKES .$
(409) /STLING *
(410) 3VENSSON ,
(411) #AMEJO ' !:
(412) A NOVEL 00!2ALPHAGAMMA AGONIST WITH BENElCIAL EFFECTS ON INSULIN RESISTANCE AND CARBOHYDRATE AND LIPID METABOLISM IN OBOB MICE AND OBESE :UCKER RATS * ,IPID 2ES :UCKERMAN 3(
(413) +AUFFMAN 2&
(414) %VANS '& 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA
(415) GAMMA COAGONIST ,9 INHIBITS MACROPHAGE ACTIVATION AND ATHEROSCLEROSIS IN APOLIPOPROTEIN % KNOCKOUT MICE ,IPIDS 'ROOT 0(
(416) VAN 6LIJMEN "*
(417) "ENSON '-
(418) (OFKER -(
(419) 3CHIFFELERS 2
(420) 6IDGEON (ART -
(421) (AVEKES ,- 1UANTITATIVE ASSESSMENT OF AORTIC ATHEROSCLEROSIS IN !0/% ,EIDEN TRANSGENIC MICE AND ITS RELATIONSHIP TO SERUM CHOLESTEROL EXPOSURE !RTERIOSCLER 4HROMB 6ASC "IOL VAN 6LIJMEN "*
(422) VAN DEN -AAGDENBERG !-
(423) 'IJBELS -*
(424) VAN DER "(
(425) (OGEN%SCH (
(426) &RANTS 22
(427) (OFKER -(
(428) (AVEKES ,- $IET INDUCED HYPERLIPOPROTEINEMIA AND ATHEROSCLEROSIS IN APOLIPOPROTEIN % ,EIDEN TRANSGENIC MICE * #LIN )NVEST VAN 6LIJMEN "*
(429) 0EARCE .*
(430) "ERGO -
(431) 3TAELS "
(432) 9ATES *7
(433) 'RIBBLE !$
(434) "OND "#
(435) (OFKER -(
(436) (AVEKES ,-
(437) 'ROOT 0( !POLIPOPROTEIN % ,EIDEN TRANSGENIC MICE AS A TEST MODEL FOR HYPOLIPIDAEMIC DRUGS !RZNEIMITTELFORSCHUNG -ATTHEWS $2
(438) (OSKER *0
(439) 2UDENSKI !3
(440) .AYLOR "!
(441) 4REACHER $&
(442) 4URNER 2# (OMEOSTASIS MODEL ASSESSMENT INSULIN RESISTANCE AND BETA CELL FUNCTION FROM FASTING PLASMA GLUCOSE AND INSULIN CONCENTRATIONS IN MAN $IABETOLOGIA +OCKX -
(443) 'ERVOIS 00
(444) 0OULAIN 0
(445) $ERUDAS "
(446) 0ETERS *-
(447) 'ONZALEZ &*
(448) 0RINCEN (-
(449) +OOISTRA 4
(450) 3TAELS " &IBRATES SUPPRESS lBRINOGEN GENE EXPRESSION IN RODENTS VIA ACTIVATION OF THE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA "LOOD 0AIGEN "
(451) -ORROW !
(452) (OLMES 0!
(453) -ITCHELL $
(454) 7ILLIAMS 2! 1UANTITATIVE ASSESSMENT OF ATHEROSCLEROTIC LESIONS IN MICE !THEROSCLEROSIS 6OLGER /,
(455) -ENSINK 20
(456) 0LAT *
(457) (ORNSTRA '
(458) (AVEKES ,-
(459) 0RINCEN (- $IETARY VEGETABLE OIL AND WOOD DERIVED PLANT STANOL ESTERS REDUCE ATHEROSCLEROTIC LESION SIZE AND SEVERITY IN APO% ,EIDEN TRANSGENIC MICE !THEROSCLEROSIS +LEEMANN 2
(460) 0RINCEN (-
(461) %MEIS **
(462) *UKEMA *7
(463) &ONTIJN 2$
(464) (ORREVOETS !*
(465) +OOISTRA 4
(466) (AVEKES ,- 2OSUVASTATIN REDUCES ATHEROSCLEROSIS DEVELOPMENT BEYOND AND INDEPENDENT OF ITS PLASMA CHOLESTEROL LOWERING EFFECT IN !0/% ,EIDEN TRANSGENIC MICE EVIDENCE FOR ANTIINmAMMATORY EFFECTS OF ROSUVASTATIN #IRCULATION $ELSING $*
(467) 0OST 3-
(468) 'ROENENDIJK -
(469) 3OLAAS +
(470) VAN DER "(
(471) VAN $UYVENVOORDE 7
(472) DE 7IT %#
(473) "LOKS 67
(474) +UIPERS &
(475) (AVEKES ,-
(476) 0RINCEN (- 2OSUVASTATIN REDUCES PLASMA LIPIDS BY INHIBITING 6,$, PRODUCTION AND ENHANCING HEPATOBILIARY LIPID EXCRETION IN !PO% LEIDEN MICE * #ARDIOVASC 0HARMACOL 6ERSCHUREN ,
(477) +LEEMANN 2
(478) /FFERMAN %(
(479) 3ZALAI !*
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