Current knowledge into the role of the peptidylarginine deiminase (PAD) enzyme family in cardiovascular disease

Al-U’datt, Doa’a G.F.; Allen, Bruce G.; Hiram, Roddy; Alrabadi, Nasr

doi:10.1016/j.ejphar.2020.173765

Cited by 13 publications

(6 citation statements)

References 92 publications

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“… 19 However, although some targets (including resolution biomarkers, peptidyl-arginine deiminase, or transglutaminase 2) are proposed in various basic research articles, no available strategy allows an efficient clinical removal of atrial fibrosis to prevent or cure AF. 12 , 20 , 21 Persistent PAB leads to chronic RA volume overload generating a mechanical stretch and stress to the RA myocardium, which may lead to the activation of an inflammatory response in the RA. 2 , 19 Recent studies support the idea that prolonged RA remodelling might be associated with the persistence of AF via aggravation of RA inflammation.…”

Section: Discussionmentioning

confidence: 99%

Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease

Le Quilliec,

LeBlanc,

Neuilly

et al. 2024

Europace

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Context Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes’ (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). RHD and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. Hypotheses RHD generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility. Methods Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, Connexin-43 (Cx43) levels, and CM morphology. RA levels of selected genes and proteins were obtained by qPCR and Western-blot respectively. Results PAB induced severe RHD identified by RV and RA hypertrophy. PAB rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated, and hypercontractile. RA CM from PAB animals showed significant augmentation of mRNA and protein levels of proinflammatory interleukin (IL)-6 and IL1β. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and junctophilin-2 (JPH2) were decreased in RA CM from PAB compared to sham rats. Conclusions RHD-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.

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Section: Discussionmentioning

confidence: 99%

Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease

Le Quilliec,

LeBlanc,

Neuilly

et al. 2024

Europace

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“…Calcium is also a major component of the atherosclerotic plaque. It can be released intra-cellularly under certain conditions present both in RA and atherosclerosis, including immune cell activation and apoptosis [ 32 , 33 ]. A recent study has proposed a direct role of MHCII containing the Shared Epitope in promoting citrullination by its interaction with calreticulin, an innate immune receptor that can initiate a signal transduction cascade leading to calcium mobilization.…”

Section: Discussionmentioning

confidence: 99%

The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis

Blackler

Akingbasote

Cairns

et al. 2023

Journal of Translational Autoimmunity

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“…The PADI family includes five isozymes, PADI1, PADI2, PADI3, PADI4, and PADI6. Each PADI has biased expression among different tissues and has been proven to play critical roles in multiple diseases, including rheumatoid arthritis, Alzheimer's disease, ulcerative colitis, and cancers (Horibata et al, 2012;Mondal and Thompson, 2019;Curran et al, 2020;Al-U'datt et al, 2021). PADI6 is uniquely and highly expressed in different stages of oocytes and cleavage stage embryos, which suggests its specific role in oocyte maturation and early embryonic development (Xu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Novel Homozygous PADI6 Variants in Infertile Females with Early Embryonic Arrest

Wang

Pang

et al. 2022

Front. Cell Dev. Biol.

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Early embryonic arrest denotes premature termination of development in preimplantation embryos, which is one of the major phenotypes of recurrent assisted reproduction failure. Padi6 is proven to be a member of the subcortical maternal complex (SCMC) in mice, which is essential in oocyte maturation and embryogenesis. We and other groups previously found that biallelic mutations in PADI6 caused female infertility manifesting as early embryonic arrest. In this study, we identified two novel homozygous variants (p.Cys163Arg, and p. Trp475*) of PADI6 in two infertile patients from a cohort of 75 females with the phenotype of early embryonic arrest. An in vitro expression study indicated severe decrease of PADI6, which might destruct the stability of SCMC. Our study expands the mutational spectrum of PADI6 and further supports the causality between PADI6 mutations and female infertility.

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Current knowledge into the role of the peptidylarginine deiminase (PAD) enzyme family in cardiovascular disease

Cited by 13 publications

References 92 publications

Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease

Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease

The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis

Novel Homozygous PADI6 Variants in Infertile Females with Early Embryonic Arrest

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