PPARγ agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice

被引:155
作者
Ryan, MJ
Didion, SP
Mathur, S
Faraci, FM
Sigmund, CD
机构
[1] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Pharmacol, Iowa City, IA 52242 USA
[3] Univ Iowa, Dept Physiol & Biophys, Iowa City, IA 52242 USA
[4] Univ Iowa, Roy J & Lucille A Carver Coll Med, Ctr Cardiovasc, Iowa City, IA 52242 USA
关键词
nitric oxide; angiotensin; endothelin; carotid;
D O I
10.1161/01.HYP.0000116303.71408.c2
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
The peroxisome proliferator activated receptor (PPARgamma) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone ( 25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R(+)A(+)). Rosiglitazone decreased systolic (138 +/- 5 versus 128 +/- 5 mm Hg) and mean blood pressure (145 +/- 5 versus 126 +/- 7 mm Hg) of R+ A(+) mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R+ A(+) mice when compared with littermate controls (RA(-)). There were no effects of rosiglitazone on RA(-) mice; however, relaxation to acetylcholine (49 +/- 10 versus 82 +/- 9% at 100 mumol/L) and nitric oxide (51 +/- 11 versus 72 +/- 6% at 10 mumol/L) was significantly improved in treated R(+)A(+) mice. Rosiglitazone treatment of R+ A(+) mice did not alter the expression of genes, including endothelial nitric oxide synthase ( eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R+ A(+) and RA(-) mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPARgamma-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester (200 mumol/L) or the PPARgamma antagonist bisphenol A diglycidyl ether; 4,4'-isopropylidenediphenol diglycidyl ether (100 mumol/L). These data suggest that in addition to potential genomic regulation caused by PPARgamma activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.
引用
收藏
页码:661 / 666
页数:6
相关论文
共 32 条
[1]   Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension [J].
Barroso, I ;
Gurnell, M ;
Crowley, VEF ;
Agostini, M ;
Schwabe, JW ;
Soos, MA ;
Maslen, GL ;
Williams, TDM ;
Lewis, H ;
Schafer, AJ ;
Chatterjee, VKK ;
O'Rahilly, S .
NATURE, 1999, 402 (6764) :880-883
[2]   Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen [J].
Baumbach, GL ;
Sigmund, CD ;
Faraci, FM .
HYPERTENSION, 2003, 41 (01) :50-55
[3]   BLOOD-PRESSURE-LOWERING BY PIOGLITAZONE - EVIDENCE FOR A DIRECT VASCULAR EFFECT [J].
BUCHANAN, TA ;
MEEHAN, WP ;
JENG, YY ;
YANG, D ;
CHAN, TM ;
NADLER, JL ;
SCOTT, S ;
RUDE, RK ;
HSUEH, WA .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 96 (01) :354-360
[4]   Peroxisome proliferator-activated receptor γ ligands increase release of nitric oxide from endothelial cells [J].
Calnek, DS ;
Mazzella, L ;
Roser, S ;
Roman, J ;
Hart, CM .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2003, 23 (01) :52-57
[5]   Quantification of mRNA for endothelial NO synthase in mouse blood vessels by real-time polymerase chain reaction [J].
Chu, Y ;
Heistad, DD ;
Knudtson, KL ;
Lamping, KG ;
Faraci, FM .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2002, 22 (04) :611-616
[6]   The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes [J].
Davisson, RL ;
Yang, GY ;
Beltz, TG ;
Cassell, MD ;
Johnson, AK ;
Sigmund, CD .
CIRCULATION RESEARCH, 1998, 83 (10) :1047-1058
[7]   Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway [J].
Delerive, P ;
Martin-Nizard, F ;
Chinetti, G ;
Trottein, F ;
Fruchart, JC ;
Najib, J ;
Duriez, P ;
Staels, B .
CIRCULATION RESEARCH, 1999, 85 (05) :394-402
[8]   Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice [J].
Didion, SP ;
Ryan, MJ ;
Didion, LA ;
Fegan, PE ;
Sigmund, CD ;
Faraci, FM .
CIRCULATION RESEARCH, 2002, 91 (10) :938-944
[9]   Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen [J].
Didion, SP ;
Ryan, MJ ;
Baumbach, GL ;
Sigmund, CD ;
Faraci, FM .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2002, 283 (04) :H1569-H1576
[10]   Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen [J].
Didion, SP ;
Sigmund, CD ;
Faraci, FM .
STROKE, 2000, 31 (03) :760-764