Abstract 345: Role Of Vascular Smooth Muscle Cell PPARγ In Aldosterone-induced Vascular Injury
Background: Peroxisome proliferator activated receptor γ (PPARγ) agonists improve vascular remodeling and endothelial dysfunction in hypertensive rodents and humans. PPARγ activation in vascular smooth muscle cells (VSMC) may be responsible for the vascular protective effects of PPARγ agonists. We previously observed a protective role of VSMC PPARγ in angiotensin II-induced endothelial dysfunction and vascular remodeling. However, it is unknown whether VSMC PPAR plays a similar protective role in adverse vascular effects of aldosterone. We hypothesized that inactivation of the Ppar gene in VSMC (smPparγ-/-) would exaggerate aldosterone-induced vascular injury.
Methods: Using a tamoxifen-inducible Cre/loxP system, Pparγ was ablated in VSMC of adult mice. Thirteen week-old control and smPparγ-/- mice were infused or not with aldosterone (400 μg/kg/d, SC) for 14 days while receiving 1% NaCl/0.3% KCl in drinking water. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) by pressurized myography.
Results: Endothelium-dependent relaxation (EDR) responses to acetylcholine were reduced to a similar extent in smPparγ-/- and aldosterone-treated control and smPparγ-/- mice compared to control mice (Emax: 62.5±8.7%, 50.8±8.6% and 56.8±7.9%, respectively, vs 86.4±3.2%, P<0.05). L-NAME, an inhibitor of nitric oxide (NO) synthase, completely blocked EDR in the four groups. Endothelium-independent relaxation response to the NO donor sodium nitroprusside and contractile responses to norepinephrine were similar in the four groups. Preliminary data indicated that aldosterone tended to increase MA stiffness in control mice, as shown by a leftward shift of the stress/strain relationship curve (strain at 140 mmHg, 0.79±0.07 vs 0.89±0.03). Furthermore, Pparγ deletion induced an increase in MA stiffness compared to control, which was not worsened by aldosterone (strain at 140 mmHg, 0.67±0.01, 0.65±0.03, vs 0.89±0.03).
Conclusion: These results indicate that either VMSC Pparγ inactivation or aldosterone treatment induce vascular remodeling and endothelial dysfunction, which are not mutually exaggerated. This suggests that PPARγ and aldosterone signal intracellularly through different pathways.
Author Disclosures: S. Ouerd: None. M. Trindade: None. N. Idris-Khodja: None. T. Barhoumi: None. S. Offermanns: None. F.J. Gonzalez: None. P. Paradis: None. E.L. Schiffrin: None.
- © 2014 by American Heart Association, Inc.