Abstract 443: Peroxisome Proliferator Activated Receptor-α Gene Deletion Exacerbates the Progression of Hypertension and Inflammation in Chronic Angiotensin II-Hypertensive Mice
The anti-inflammatory properties of peroxisome proliferator activated receptor- (PPAR-α) contribute to the incidence of hypertension and its associated cardiovascular disease. Fenofibrate, a PPAR-α agonist has been demonstrated to reduce angiotensin II (Ang II)-induced hypertension via inducing cytochrome P450 4A (CYP4A) and increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. The current study determines whether deletion of PPAR-α gene exacerbates the elevation in blood pressure, plasma interleukin-6 (IL-6) levels, and renal inflammatory markers during infusion of a slow-pressor dose of Ang II (400 ng/kg/min). Ten to twelve week old male PPAR-α knockout (KO) mice and their B129s wild-type (WT) controls were implanted with telemetry devices and infused with Ang II for 12 days. There was no difference in basal mean arterial pressure (MAP) between WT and PPAR-α KO mice compared to WT (113 ± 1 vs. 111 ± 2 mmHg). On day 14 of Ang II infusion, MAP was elevated in PPAR-α KO mice compared to WT (160 ± 3 vs. 142 ± 4 mmHg, P < 0.05) and fenofibrate administration significantly reduced the elevation in MAP in WT + Ang II mice (134 ± 7 mmHg, P < 0.05) with no significant effect on PPAR-α KO + Ang II mice (158 ± 8 mmHg). Plasma IL-6 levels were significantly higher in PPAR-α KO mice when compared to WT on day 12 of Ang II infusion (30 ± 4 vs. 8 ± 2 pg/ml, P < 0.05) and fenofibrate significantly reduced plasma IL-6 in Ang II-treated WT mice (10 ± 3 pg/ml, P < 0.05) with no significant effect in Ang II-treated PPAR-α KO mice (28 ± 4 pg/ml). Fenofibrate significantly increased renal expression of CYP4A and restored the decrease in renal CYP2J expression in WT + Ang II treated mice with no effect on PPAR-α KO + Ang II. Fenofibrate also significantly reduced the elevation in renal expression of the inflammatory markers intracellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and cyclooxygenase-2 (COX-2) in WT + Ang II mice. Our results demonstrate that PPAR-α KO mice have a greater presser response during Ang II hypertension and activation of PPAR-α attenuates Ang II-induced hypertension possibly via up-regulation of renal CYP4A and CYP2J and anti-inflammatory mechanisms involving reducing the inflammatory markers IL-6, MCP-1, ICAM-1 and COX-2.
- © 2012 by American Heart Association, Inc.