S-nitrosylation of paired-related homeobox 1 promotes cardiac remodeling following myocardial infarction

TL;DR

This study shows that S-nitrosylation of Prrx1 promotes heart tissue changes after a heart attack, suggesting it could be a target for new treatments.

Contribution

The study identifies Prrx1 S-nitrosylation as a novel mechanism driving cardiac remodeling after myocardial infarction.

Findings

Prrx1 S-nitrosylation at cysteine 207 increases Wnt5a expression and fibroblast-to-myofibroblast differentiation.

Inhibiting Prrx1 S-nitrosylation reduces cardiac fibrosis and improves heart function in mice after MI.

Prrx1 S-nitrosylation is elevated in human patients following myocardial infarction.

Abstract

Cardiac remodeling, mediated by fibroblast-to-myofibroblast differentiation, is a key pathophysiologic step to determine the prognosis of patients following myocardial infarction (MI). Paired-related homeobox 1 (Prrx1) is a master transcription factor of fibroblasts for myofibroblastic lineage progression. Protein S-nitrosylation by nitric oxide (NO) is highly related to regulate cellular functions. This study is to investigate whether and how Prrx1 S-nitrosylation plays a key role in postischemic remodeling of heart.

The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac fibrosis was assessed using Masson staining. Heart function was measured by echocardiography.

MI induced cardiac remodeling as cardiac fibrosis and heart dysfunction in mice, accompanied with increased Prrx1 transcriptional activity, but inhibited by N-acetyl-cysteine administration. In recombinant human protein, NO donors increased Prrx1 S-nitrosylation at cysteine 207 (C207). In human cardiac fibroblasts, oxygen-glucose deprivation or transforming growth factor beta upregulated NO productions, Prrx1 S-nitrosylation, Prrx1 transcriptional activity, Wnt5a gene expression, and fibroblast-to-myofibroblast differentiation, which were abolished by Prrx1-C207R mutant. In vivo, exogenous expression of Prrx1-C209R alleviated MI-induced cardiac fibrosis and promoted the recovery of heart functions in mice. Fibroblast-specific Prrx1 gene knockout prevented cardiac fibrosis and heart dysfunctions in mice fowling MI. In human patients with post-MI, Prrx1 S-nitrosylation was increased.

Upregulation of Prrx1 by S-nitrosylation increases Wnt5a gene expression to induce fibroblast-to-myofibroblast differentiation, which contributes to cardiac remodeling after MI. In perspective, targeting Prrx1 S-nitrosylation should be considered to improve the outcome of patients with MI.

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