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Vascular dysfunction in transgenic mice expressing a PPARγ interfering mutation specifically in vascular muscle: role of aortic rho kinase
Author(s) -
Ketsawatsomkron Pimonrat,
Lange Willem J.,
Pelham Christopher J.,
Halabi Carmen M.,
Faraci Frank M.,
Sigmund Curt D.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.952.10
Subject(s) - myograph , rho associated protein kinase , sodium nitroprusside , medicine , endocrinology , aorta , vascular smooth muscle , thoracic aorta , endothelial dysfunction , vasodilation , contraction (grammar) , acetylcholine , mesenteric arteries , kinase , chemistry , artery , nitric oxide , biochemistry , smooth muscle
PPARγ is a ligand activated transcription factor expressed in vascular muscle and endothelium. We previously reported that targeted expression of a dominant negative PPARγ mutation in vascular muscle (S‐P467L) of transgenic mice caused severe aortic dysfunction. This included impaired responses to acetylcholine (ACh), sodium nitroprusside (SNP) and cGMP. Using a pressurized myograph preparation in vitro we now show that the mesenteric artery (~190μm) exhibits impaired relaxation to 1 μM ACh (22±6% S‐P467 vs 74±5% WT), but a normal response to 10 μM SNP (89±9% S‐P467L vs 79±11% WT), suggesting the mechanisms regulating vascular function by PPARγ may differ among vascular beds. We also reported that aorta from S‐P467L mice exhibited augmented contraction to ET‐1, which was rho kinase dependent. NO is thought to be an endogenous inhibitor of rho kinase. We therefore tested the hypothesis that inhibition of rho kinase may restore the response to NO in thoracic aorta from S‐P467L mice. Vehicle‐treated S‐P467L aorta exhibited impaired relaxation to ACh (5±3% vs 71±1% in WT). Y27632 (3 μM) caused improved relaxation to ACh (40±3%) in aorta from S‐P467L, but had no effect in aorta from WT. A similar improvement in relaxation to SNP was also observed (75±6% Y27632 vs 38±5% vehicle) in S‐P467L. These data implicate increased activity of the rho kinase pathway in mediating impaired responses to NO in the aorta of S‐P467L mice.