Background and Aim. Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Due to the heterogeneous nature and complexity of fibrotic remodeling processes, the knowledge of the underlying molecular mechanisms is still limited. Thus, effective pharmacotherapy to prevent or reverse fibrosis is missing. The objective of this study was to decipher the mechanistic interplay between polo-like kinase 2 (PLK2) and the pro-fibrotic cytokine osteopontin (OPN) in the pathogenesis of atrial fibrosis and atrial fibrillation to derive novel therapeutic targets.

Methods and Results. This study was based on human atrial tissue biopsies, human peripheral blood samples, a PLK2 knockout mouse model, a canine tachy-pacing model and specific pharmacological interventions on human and murine cardiac fibroblasts. Compared to sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from AF patients showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation (Fig. 1 a, b). Confirmatory analysis of tissue samples of a canine tachy-pacing model showed PLK2 downregulation exclusively in the atria but not in the ventricles. Both, genetic deletion and pharmacological inhibition of PLK2 induced pro-fibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN identified by discovery proteomics (Fig. 1 c). In line with these findings, OPN plasma levels were significantly elevated in AF patients with atrial fibrosis compared to those without and SR controls (Fig. 1 d, e). Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. The histological analysis of whole heart sections revealed pronounced atrial and ventricular fibrosis in PLK2 KO animals compared to their WT littermates (Fig. 1 f). Furthermore, PLK2 KO mice showed left atrial dilation during echocardiography (Fig. 1 g). Consequently, PLK2-deficient animals were prone to experimentally induced AF (Fig. 1 h).

Conclusion and Clinical Impact. In summary, abnormal PLK2-ERK1/2-OPN axis function critically contributes to AF-related atrial fibrosis and dilation. Our results strengthen the current hypothesis that atrial fibrillation is not only an ion channel disease but also a complex systemic disorder. Restoration of physiological PLK2 expression and/or blockade of osteopontin release may constitute innovative targets to prevent fibrosis progression in AF.