Abstract 16227: A Chemokine C-C motif receptor 2 Antagonist, INCB3344, Reverses Hypertension and Macrophage Accumulation in the Artery Wall in Angiotensin II-Treated Mice
Macrophages accumulate in the artery wall during hypertension and contribute to the vascular inflammation, oxidative stress and endothelial dysfunction that are hallmarks of the condition. The aim of the present study was to identify chemokine ligand-receptor interactions responsible for macrophage influx during hypertension and to provide proof-of-concept that inhibition of these interactions is a viable approach for treating the condition. Male C57BL6/J mice were infused with Ang II (0.7 mg/kg/d, s.c.) or saline for up to 28 d. Systolic BP was measured by tail cuff plethysmography, expression levels of chemokines and chemokine receptors were assessed by real-time PCR, and leukocyte populations in the vascular wall were analyzed by flow cytometry. Ang II infusion caused a marked increase in systolic BP that reached a plateau within 3-5 days and remained elevated for the remainder of the treatment period (158±3 mmHg vs 116±2 mmHg in saline group; n≥21, P<0.05). A PCR array revealed that Ang II-induced hypertension was associated with a 2-fold increase in aortic expression of chemokine C-C motif receptor 2 (CCR2) and its ligand, CCL8, and these findings were subsequently confirmed with real-time PCR (n=11, P<0.05 for both genes). Ang II-induced hypertension was also associated with a 2.5-fold increase in total macrophage (CD45+CD11b+F480+) numbers in the aortic wall (n=16; P<0.05) and ∼30% of these cells were CCR2-positive. Treatment of mice with a small molecule antagonist of CCR2, INCB3344 (30 mg/kg/d, i.p.), 7 d after the induction of hypertension with Ang II, reduced the accumulation of macrophages in the artery wall by ∼50% (n≥8; P<0.05). Moreover, INCB3344 treatment rapidly (within 7 d) lowered elevated systolic BP in Ang II-treated mice by 20-25 mmHg (i.e. 50-60%), and BP remained at this reduced level until the end of the 28 d treatment period (n=4-5; P<0.05). Thus, CCR2 is an important regulator of both macrophage accumulation in the artery wall and systolic BP during Ang II-induced hypertension, highlighting it as a promising target for future anti-hypertensive therapies.
- © 2012 by American Heart Association, Inc.