24 January 2020 : Animal Research
Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats
Zuowang Ma1ABCDE, Kai Zhang1ABDE, Yun Wang1ABC, Weiding Wang1AB, Yu Yang1AB, Xue Liang1AB, Yue Zhang1AB, Guangping Li1AFG*DOI: 10.12659/MSM.918883
Med Sci Monit 2020; 26:e918883
Abstract
BACKGROUND: The structural remodeling of atrial architecture, especially increased amounts of fibrosis, is a critical substrate to atrial fibrillation (AF). Doxycycline (Doxy) has recently been shown to exert protective effects against fibrogenic response. This study investigated whether doxycycline (Doxy) can sufficiently ameliorate the fibrosis-induced changes of atrial conduction and AF vulnerability in a chronic intermittent hypoxia (CIH) rat model.
MATERIAL AND METHODS: Sixty rats were randomized into 3 groups: Control, CIH, and CIH with Doxy treatment (DOXY) group. CIH rats were exposed to CIH (6 h/d) and Doxy-treated rats were treated with Doxy during processing CIH. After 6 weeks, echocardiographic and hemodynamic parameters were measured. Isolated atrial epicardial activation mapping and heart electrophysiology were performed. The extent of atrial interstitial fibrosis were estimated by Masson’s trichrome staining. The expression levels of TGF-β1 and downstream factors were determined by real-Time PCR, immunohistochemistry, and Western blot analysis.
RESULTS: Compared to Control rats, the CIH rats showed significant atrial interstitial fibrosis, longer inter-atrial conduction time, and elevated conduction inhomogeneity and AF inducibility, and the expression of TGF-β1, TGF-βRI, TGF-βRII, P-Smad2/3, α-SMA, CTGF, and Collagen I were significantly increased, whereas the velocity of atrial conduction and the expression of miR-30c were dramatically decreased. All of these changes were significantly improved by Doxy treatment.
CONCLUSIONS: The findings suggested that Doxy can profoundly mitigate atrial fibrosis, conduction inhomogeneity as well as high AF inducibility secondary to fibrosis in a CIH rat model through suppressing the TGF-β1 signaling pathway.
Keywords: Atrial Fibrillation, doxycycline, Receptors, Transforming Growth Factor beta, Atrial Remodeling, Fibrosis, Heart Atria, Heart Rate, Transforming Growth Factor beta
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