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

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BACKGROUNDS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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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