Abstract 11612: Ablation of Angiotensin IV Receptor (AT4R) Augments Angiotensin II-Induced Myocardiac Fibrosis and Cardiac Dysfunction
The angiotensin II (Ang II)-AngII receptor type1 (AT1R) axis plays a key role in cardiac inflammation and fibrosis in chronic heart diseases. Insulin-regulated aminopeptidase (IRAP), a pleiotropic aminopeptidase capable of metabolizing several peptide substrates, has been identified as Ang IV receptor (AT4R). We hypothesized that the AngIV-AT4R axis is a negative regulator of Ang II-mediated signaling and its adverse effects on the cardiovascular system.
[Methods and Results] [in vitro] In cultured cardiac fibroblasts, IRAP protein levels were eleveted in wild type mice (WT, C57BL6/J) after AngII treatment (10-6M for 24h), while both AT1R and AT2R levels were elevated (2.6- and 3.4-fold, respectively) only in IRAP knockout (IRAP-/-) mice. Coadminstration with AT1R blocker, Candesartan (CAN, 10-6M), reversed the elevation of IRAP in WT and AT1R in IRAP-/- mice. The levels of Mas receptor and ACE2 did not alter during the observation period. [in vivo-1] Mice at 10 weeks of age were infused with AngII, AngIV, (1.4 mg/kg/day each), or saline for 4 weeks (n=12 each). Saline and AngIV infusion did not alter the parameters of hemodynamics and cardiac morphology. AngII infusion significantly elevated blood pressure (BP) in either mice with a greater degree in IRAP-/- (WT: IRAP-/- = 102±9.5 to 128±18: 108±9.6 to 151±18* mmHg, *P=0.032 vs. WT). Perivascular and interstitial cardiac fibrosis was deteriorated in IRAP-/- as compared to WT in accordance with activation of TGF-β and NFκB (phosphorylated IκB-α). The prominent cardiac dysfunction in IRAP-/- was confirmed by serial echographic analyses. [in vivo-2] To assess the effects of pressure overload on myopathy, CAN (1.0 mg/kg/day) or nonspecific vasodilator (Hydralazine: HDR, 25 mg/kg/day) was administered to AgII-infused IRAP-/- (n=8 each). Perivascular and interstitial cardiac fibrosis were less in the CAN group than HDR group (0.61% vs. 3.8% fibrosis per area, P=0.0012), despite comparable BP reduction and cardiac morphology.
[Conclusions] Our findings demonstrate that ablation of AT4R promotes inflammation and myocardiac fibrosis mainly due to elevated AngII levels and increased AT1R signaling, and suggest a protective role of the AngIV-AT4R axis acting as a counterpart of Ang II-mediated signaling.
- © 2011 by American Heart Association, Inc.