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- W2971366306 abstract "Targeting the angiotensin type 2 receptor (AT 2 R) evokes anti-fibrotic effects in various organs. A single β-amino acid substitution for proline in angiotensin III (β-Pro 7 -Ang III) markedly improved the AT 2 R:AT 1 R selectivity over 20,000-fold. Additionally, tryptophan substitution in position 8 (β-Pro 7 -Trp 8 -Ang III) further improved the AT 2 R:AT 1 R selectivity, while a D-arginine substitution (D-Arg 2 - β-Pro 7 -Trp 8 -Ang III) or N-Acetyl attachment (N-Ac-β-Pro 7 -Trp 8 -Ang III) increased in vitro plasma stability. The aim of this study was to determine the anti-fibrotic effects of these novel AT 2 R selective ligands (β-Pro 7 -Trp 8 -Ang III; D-Arg 2 -β-Pro 7 -Trp 8 -Ang III; N-Ac-β-Pro 7 -Trp 8 -Ang III) in vitro and in high salt (HS) diet-induced heart and kidney disease. Human cardiac fibroblasts (HCFs) were treated with TGF-β1 in the absence or presence of ligands for 72 hours. Collagen levels in HCFs were measured by Western blot analysis. Male FVB/N mice were subjected to 8 weeks of HS (5%)-induced cardiac and renal fibrosis. From weeks 5-8, sub-groups of mice (n=8-9/group) were treated with either β-Pro 7 -Trp 8 -Ang III, D-Arg 2 -β-Pro 7 -Trp 8 -Ang III or N-Ac-β-Pro 7 -Trp 8 -Ang III (all 0.1 mg/kg/day) via subcutaneous mini-pumps. Various markers of cardiac and renal inflammation, fibrosis, and collagen turnover were measured. All peptides markedly reduced TGF-β1-induced collagen I production in HCFs (all P<0.05 vs. TGF-β1). Compared with normal salt (NS), HS increased cardiac collagen by hydroxyproline (from 1.5 ± 0.05 to 2.2±0.08 % collagen/dry tissue weight) and picrosirius red (from 4.8±0.36% to 6.9±0.59% of area) analyses (both P<0.05). Each peptide reversed fibrosis (all P<0.05 vs HS; both methods) and similar anti-fibrotic effects of all peptides occurred in kidneys. These effects were associated with reduced myofibroblast differentiation (α-SMA) in heart and kidney (all P<0.05 vs HS). Moreover, HS-induced cardiac and renal inflammation (p-IκB and F4/80 immunofluorescence) were increased by 50%-80% (from NS of 1.5-2% area); all indices were reversed by each peptide (all P<0.05). In conclusion, highly AT 2 R-selective ligands were cardio- and reno- protective, highlighting the therapeutic strategy of AT 2 R stimulation to treat organ fibrosis." @default.
- W2971366306 created "2019-09-12" @default.
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- W2971366306 date "2019-09-01" @default.
- W2971366306 modified "2023-10-05" @default.
- W2971366306 title "Abstract 101: Novel AT2 Receptor Agonists are Cardio- and Reno-Protective <i>In Vitro</i> and <i>In Vivo</i>" @default.
- W2971366306 doi "https://doi.org/10.1161/hyp.74.suppl_1.101" @default.
- W2971366306 hasPublicationYear "2019" @default.
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