Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats

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/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-b1 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-b1, TGF-bRI, TGF-bRII, P-Smad2/3, a-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-b1 signaling pathway.

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats

“…However, due to its wide range of nonantibiotic properties and relative safety profile, extensive pre-clinical and clinical studies have been investigating doxycycline therapeutic approaches, with promising results. Reports in several medical settings have shown ameliorating the severity of diabetic retinopathy [ 44 ] and proliferative vitreoretinopathy [ 45 ], inhibiting the proliferation and proapoptotic effect in human cancer cells [ 46 , 47 , 48 , 49 ], positive effects on osteoarthritis and posttraumatic arthritis progression [ 50 ], and reduction of cardiac dysfunction in different models of heart damage [ 22 , 51 , 52 ].…”

CircRNA_0263 and circRNA_1507 are Dysregulated in Atrial Fibrosis Rat Induced by Chronic Intermittent Hypoxia

“…Clinical studies have shown that patients with OSA are vulnerable to the incidence of AF [24,25]. CIH, which is a hallmark of OSA, has been associated with the development of brosis in multiple tissues, including the myocardium [20,26], systemic vasculature [27], liver [28], and lungs [29]. Intermittent hypoxia for a period as short as 4-5 weeks can cause diffuse collagen ber deposition in rats [29,30].…”

“…The rats were allowed free access to food and water and provided with a normal diet. The atrial brosis rat model was established by exposure to a CIH environment, using a previously described protocol [20]. Brie y, the rats in the CIH group were placed in a chamber lled with alternating cycles of nitrogen and oxygen, whereas the control group rats were maintained under normal oxygen conditions.…”

Hypoxia signaling in human health and diseases: implications and prospects for therapeutics

“…Atrial fibrillation (AF) is one of the most frequent forms of human arrhythmias, with a significant disability and fatality rate in patients. 393,396,397 The etiology of AF is linked to MMP-9; the increased activity of MMP-9 causes atrial fibrosis and induces AF. 398 Another study demonstrated that HIF-1α stimulates the downstream factor TGF-β1 by promoting the expression of angiotensin II (Ang II), which causes high expression of MMP-9.…”