Peptidyl arginine deiminase inhibition alleviates angiotensin II-induced fibrosis.
PAD inhibitor
Peptidyl arginine deiminase (PAD)
cardiac fibrosis
mass spectrometry
proteomics
Journal
American journal of translational research
ISSN: 1943-8141
Titre abrégé: Am J Transl Res
Pays: United States
ID NLM: 101493030
Informations de publication
Date de publication:
2023
2023
Historique:
received:
01
03
2023
accepted:
14
06
2023
medline:
10
8
2023
pubmed:
10
8
2023
entrez:
10
8
2023
Statut:
epublish
Résumé
The conversion of protein arginine residues to citrulline by calcium-dependent peptidyl arginine deiminases (PADs) has been implicated in the pathogenesis of several diseases, indicating that PADs are therapeutic targets. A recent study indicated that PAD4 regulates age-related organ fibrosis and dysfunction; however, the specific role of this PAD and its citrullination substrate remains unclear. We investigated whether pharmacological inhibition of PAD activity could affect the progression of fibrosis and restore heart function. Cardiac hypertrophy was induced by chronic infusion of angiotensin (Ang) II. After 2 weeks of AngII infusion, a PAD inhibitor (Cl-amidine hydrochloride) or vehicle (saline) was injected every other day for the next 14 days together with the continued administration of AngII for a total of up to 28 days. Cardiac fibrosis and remodeling were evaluated by quantitative heart tissue histology, echocardiography, and mass spectrometry. A reverse AngII-induced effect was observed in PAD inhibitor-treated mice (n=6) compared with AngII vehicle-treated mice, as indicated by a significant reduction in the heart/body ratio (AngII: 6.51±0.8 mg/g vs. Cl-amidine: 5.27±0.6 mg/g), a reduction in fibrosis (AngII: 2.1-fold increased vs. Cl-amidine: 1.8-fold increased), and a reduction in left ventricular posterior wall diastole (LWVPd) (AngII: 1.1±0.04 vs. Cl-amidine: 0.78±0.02 mm). Label-free quantitative proteomics analysis of heart tissue indicated that proteins involved in fibrosis (e.g., periostin), cytoskeleton organization (e.g., transgelin), and remodeling (e.g., myosin light chain, carbonic anhydrase) were normalized by Cl-amidine treatment. Our findings demonstrate that pharmacological inhibition of PAD may be an effective strategy to attenuate cardiac fibrosis.
Types de publication
Journal Article
Langues
eng
Pagination
4558-4572Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL136737
Pays : United States
Informations de copyright
AJTR Copyright © 2023.
Déclaration de conflit d'intérêts
The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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