Genetic Deletion of Retinol‐Binding Protein 7 (RBP7), a PPARγ Target Gene, Accelerates Angiotensin II‐mediated Endothelial Dysfunction

Abstract

Mice expressing dominant-negative peroxisome proliferator-activated receptor γ (PPARγ) in endothelium exhibit an augmented pressor response to angiotensin II (Ang II). The mechanisms responsible for protective actions of PPARγ are unclear. RBP7 is an intracellular RBP and a PPARγ target gene highly expressed in endothelium. We hypothesized that RBP7 may normally mediate protective effects and that deletion of RBP7 may augment Ang II-induced endothelial dysfunction. RBP7 knockout (KO) and wild type (WT) mice were infused with subpressor or pressor doses of Ang II (120 or 1000 ng/kg/min, osmotic minipumps) or saline for 2 weeks. Systolic blood pressure (SBP) was measured using tail-cuff and carotid artery function was assessed using a wire myograph. SBP and the carotid artery responses to acetylcholine (ACh) and nitroprusside (SNP) were not different between saline-infused KO and WT mice suggesting that KO of RBP7 per se does not affect baseline vascular function. Subpressor Ang II did not alter SBP in either group, but diminished relaxation in response to ACh, but not SNP, in KO mice (at 30 µM: ACh 41±3% in KO vs 72±6% in WT, p<0.05). Pressor Ang II increased SBP (WT: 121±2 to 152±6 mmHg, KO: 128±4 to 159±6 mmHg) and impaired responses to ACh and SNP to a similar extent in both WT and KO mice. Superoxide, measured by hydroethidine staining, was significantly higher in aorta after subpressor Ang II in KO compared with WT mice, suggesting that superoxide may contribute to impaired ACh responses in KO mice. We conclude that loss of RBP7 augments Ang II-mediated endothelial dysfunction, possibly through an oxidative stress-dependent mechanism.