Doxycycline attenuates chronic intermittent hypoxia-induced atrial fibrosis in rats

Introduction: Atrial structural remodeling in the form of fibrosis contributes to the arrhythmic substrate in atrial fibrillation (AF). The aim of this study was to investigate the effects of doxycycline on chronic intermittent hypoxia (CIH)-induced atrial fibrosis and the pathophysiological mechanisms underlying such changes. Methods: A total of 30 Sprague Dawley rats were randomized into three groups: control group, CIH group, and CIH with doxycycline treatment (CIH-D) group. CIH lasted 5 hours per day for 4 weeks. CIH-D rats were administrated doxycycline for 4 weeks, while they received CIH. Masson's trichrome staining was used to determine collagen deposit in the atrial myocardium. Protein and mRNA levels of Matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9), microRNA-21 (miR-21) and its downstream target Sprouty1 (Spry1), and extracellular signal-regulated kinases 1/2 (ERK1/2) were measured using Western blotting or real-time qRT-PCR, respectively. Results: Compared to the control group, the CIH group showed higher interstitial collagen fraction, increased MMP-9, miR-21, and p-ERK1/2 levels, and decreased MMP-2 and Spry1 levels. Doxycycline treatment attenuated CIH-induced atrial fibrosis, reduced MMP-2, MMP-9, miR-21, and p-ERK1/2, and increased Spry1. Conclusions: CIH treatment induced significant atrial fibrosis in our rat model, which was attenuated by doxycycline. These changes can be explained by alterations in the MMP and miR-21/ERK signaling pathways.