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Interference with Peroxisome Proliferator Activated Receptor Gamma (PPARG) in smooth muscle causes aortic dysfunction via a Rho‐kinase‐dependent mechanism
Author(s) -
Pelham Christopher James,
Ketsawatsomkron Pimonrat,
Groh Severine,
Lange Willem J.,
Faraci Frank M.,
Sigmund Curt D.
Publication year - 2010
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.24.1_supplement.980.6
Subject(s) - rho associated protein kinase , medicine , peroxisome proliferator activated receptor gamma , endocrinology , sodium nitroprusside , chemistry , rhoa , contraction (grammar) , vascular smooth muscle , vasodilation , nitric oxide , kinase , receptor , peroxisome , biology , signal transduction , biochemistry , smooth muscle
Transgenic mice expressing a vascular muscle‐specific dominant negative mutant of PPARG (S‐P467L) develop hypertension and aortic dysfunction, supporting a protective role for PPARG in the vasculature. Aortic rings from S‐P467L mice displayed impaired vasodilation to acetylcholine (Ach) and sodium nitroprusside (SNP); and augmented contraction to endothelin‐1 (10nM ET‐1; 0.54±0.04g vs 0.16±0.03g non‐transgenic, NT. P<0.01) that was blocked by pre‐incubation with a Rho‐kinase inhibitor (1μM Y‐27632 + 10nM ET‐1; 0.13±0.02g vs 0.03±0.02g NT). Maximal contraction to PGF 2α or KCl was not altered. We tested the role of basal nitric oxide (NO) as an endogenousinhibitor of RhoA/Rho‐kinase signaling. The level of total and p‐Ser1177 eNOS protein did not differ between S‐P467L and NT aorta. NOS inhibition (L‐NAME 100μM) increased contraction of S‐P467L aorta to ET‐1 (1.30±0.06g) to a greater degree than NT (0.50±0.05g, P<0.01). Similar results were observed for PGF 2α and KCl. Rho‐kinase‐dependent phosphorylation of MYPT was enhanced in S‐P467L aorta (172±10% of NT, P<0.01). Pre‐incubation with Rho‐kinase inhibitor (1μM Y‐27632) significantly improved relaxation responses to Ach and SNP in S‐P467L aorta, but did not affect NT. We conclude that interference with PPARG in vascular muscle promotes aortic constriction through elevated Rho‐kinase activity, which is inhibited by endogenous NO.