Background and Aim. Although atrial fibrillation and subsequent fibrotic remodeling of the heart affect millions of patients worldwide, the underlying molecular mechanisms through which atrial fibrillation leads to heart remodeling and fibrosis in patients are incompletely understood. Consequently, there is a need to define novel targets for pharmacotherapy that limit the debilitating consequences of atrial fibrillation.

Methods and Results. Our study capitalized from human atrial tissue biopsies, human peripheral blood samples, a PLK2 knockout mouse model and specific pharmacological interventions on human and murine cardiac fibroblasts. In atrial tissue samples from patients with chronic atrial fibrillation, PLK2 was 50% downregulated by hypoxia-induced promoter methylation (Figure 1 a and b). In vitro, genetic deletion and pharmacological inhibition (TC-S 7005, 1 µM) of PLK2 led to strikingly reduced fibroblast proliferation, increased myofibroblast differentiation and enhanced senescence induction. Discovery proteomics revealed that genetic knockout of PLK2 resulted in de novo secretion of the inflammatory cytokine osteopontin in fibroblasts and concomitant ventricular fibrosis in the PLK2 knockout mouse model (Figure 1 c and d). We then transferred our findings from the mouse experiments and cell culture back into patients to reveal a previously undescribed disease-relevant mechanism involving PLK2. We measured elevated osteopontin in both heart tissue and the peripheral blood of atrial fibrillation patients compared to sinus rhythm controls using western blot and ELISA (Figure 1 c). Finally, we identified the Ras-ERK1/2 signaling pathway to be a promising link between reduced expression of PLK2 and elevated osteopontin secretion.

Conclusion and Clinical Impact. We identified PLK2 as an epigenetically regulated kinase involved in the pathophysiology of fibrosis in atrial fibrillation. Our results strengthen the current hypothesis that atrial fibrillation is not only an ion channel disease but a complex (systemic) inflammatory disorder. Restoration of physiological PLK2 expression or blockade of osteopontin release may constitute valuable new drug targets for the prevention and treatment of cardiac fibrosis in atrial fibrillation.