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The Potential Effects of Aliskiren on Atrial Remodeling Induced by Chronic Intermittent Hypoxia in Rats.

ABSTRACT: Purpose:Atrial remodeling takes part in the pathogenesis of atrial fibrillation (AF). Aliskiren, as a direct renin inhibitor, has been shown to exert protective effects against arrhythmia. The aim of this study was to investigate the potential role of aliskiren in atrial remodeling in a chronic intermittent hypoxia (CIH) rat model. Methods:A total of 45 Sprague-Dawley rats were randomly assigned into three groups (n=15 per group): control group; CIH group; and CIH with aliskiren (CIH-A) group. CIH and CIH-A rats were subjected to CIH for 6 h per day for 4 weeks. Atrial fibrosis was evaluated using Masson's trichrome staining. Electrophysiological tests were conducted in the isolated perfused hearts to assess the atrial effective refractory period and inducibility of AF. Atrial ionic remodeling was measured using the whole-cell patch-clamp technique, and Western blotting and real-time quantitative polymerase chain reactionwere performed to evaluate changes in ion channels. Results:CIH induced obvious collagen deposition, and the abnormal fibrosis was significantly attenuated by aliskiren. The inducibility of AF was increased significantly in the CIH group compared with the control and CIH-A groups (23±24.5% vs 2.0±4.2% vs 5.0±7.0%, respectively; P<0.05). Compared with the control group, the densites of the calcium current (I CaL) and sodium current (I Na) were reduced significantly in the CIH group (I CaL: -3.16±0.61 pA/pF vs -7.13±1.98 pA/pF; I Na: -50.97±8.71 pA/pF vs -132.58±25.34 pA/pF, respectively; all P<0.05). Following intervention with aliskiren, the reductions in I CaL and I Na were significantly improved, and the ionic modeling changes assessed at the mRNA and protein levels were also significantly improved. Conclusion:CIH could alter atrial modeling and subsequently promote the occurrence and development of AF, which could be attenuated by treatment with aliskiren.

SUBMITTER: Miao S

PROVIDER: S-EPMC7502603 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Potential Effects of Aliskiren on Atrial Remodeling Induced by Chronic Intermittent Hypoxia in Rats.

Miao Shuai S Yang Yu Y Li Ruiling R Yin Li L Zhang Kai K Cheng Lijun L Xu Xiaona X Wang Weiding W Zhao Zhiqiang Z Li Guangping G

Drug design, development and therapy 20200916

<h4>Purpose</h4>Atrial remodeling takes part in the pathogenesis of atrial fibrillation (AF). Aliskiren, as a direct renin inhibitor, has been shown to exert protective effects against arrhythmia. The aim of this study was to investigate the potential role of aliskiren in atrial remodeling in a chronic intermittent hypoxia (CIH) rat model.<h4>Methods</h4>A total of 45 Sprague-Dawley rats were randomly assigned into three groups (n=15 per group): control group; CIH group; and CIH with aliskiren ( ...[more]

PMID: 32982180

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Project description:Atrial fibrillation (AF) is the most frequent form of clinical cardiac arrhythmias. Previous evidence proved that atrial anatomical remodeling (AAR) and atrial electrical remodeling (AER) are crucial for the progression and maintenance of AF. This study is aimed at investigating the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist, Liraglutide (Lir), on atrial remodeling (AR) mouse model induced by chronic intermittent hypoxia (CIH). C57BL/6 mice were categorized randomly into the control, Lir, CIH, and CIH+Lir groups. CIH was performed in CIH and CIH+Lir groups for 12 weeks. Lir (0.3 mg/kg/day, s.c) was administered to the Lir and CIH+Lir groups for four weeks, beginning from the ninth week of CIH. Meanwhile, echocardiography and right atrial endocardial electrophysiology via jugular vein, as well as induction rate and duration of AF, were evaluated. Masson and Sirius red staining assays were utilized to assess the extent of fibrosis in the atrial tissue of the mice. Immunohistochemical staining, RT-qPCR, and Western blotting were performed to evaluate the marker levels of AAR and AER and the expression of genes and proteins of the miR-21/PTEN/PI3K/AKT signaling pathway, respectively. ELISA was also performed to evaluate the changes of serum inflammatory factor levels. The CIH group exhibited significant AR, increased atrial fibrosis, and a higher incidence rate of AF compared to the control group. Lir could significantly downregulate the protein expression level in the PI3K/p-AKT pathway and upregulated that of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Moreover, Lir downregulated the expression of miR-21. However, the protein expressions of CACNA1C and KCNA5 in atrial tissue were not changed significantly. In addition, Lir significantly attenuated the levels of markers of inflammation (TNF-α and IL-6) in the serum. In the mouse model of CIH, Lir treatment could ameliorate AR by the miR-21/PTEN/PI3K/AKT signaling pathway and modulation of inflammatory responses.

Project description:BackgroundObstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury.MethodsMale Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.ResultsCB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.ConclusionCIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.

Project description:AimChronic intermittent hypoxia (CIH) is a key characteristic of obstructive sleep apnea (OSA) syndrome, a chronic respiratory disorder. The mechanisms of CIH-induced metabolic disturbance and histopathological damage remain unclear.MethodsCIH-induced rats underwent daily 8-h CIH, characterized by oxygen levels decreasing from 21% to 8.5% over 4 min, remaining for 2 min, and quickly returning to 21% for 1 min. The control rats received a continuous 21% oxygen supply. The levels of hypersensitive C reactive protein (h-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and nuclear factor kappa-B (NF-κB) were measured by ELISA. Histological analysis of the soft palates was conducted using HE staining. The microbial profiling of fecal samples was carried out by Accu16STM assay. Untargeted metabolomics of serum and soft palate tissue samples were analyzed by UPLC-MS. The protein expression of cAMP-related pathways in the soft palate was determined by Western blot.ResultsAfter 28 h of CIH induction, a significant increase in pro-inflammatory cytokines was observed in the serum, along with mucosal layer thickening and soft palate tissue hypertrophy. CIH induction altered the diversity and composition of fecal microbiota, specifically reducing beneficial bacteria while increasing harmful bacteria/opportunistic pathogens. Notably, CIH induction led to a significant enrichment of genera such as Dorea, Oscillibacter, Enteractinococcus, Paenibacillus, Globicatella, and Flaviflexus genera. Meanwhile, Additionally, CIH induction had a notable impact on 108 serum marker metabolites. These marker metabolites, primarily involving amino acids, organic acids, and a limited number of flavonoids or sterols, were associated with protein transport, digestion and absorption, amino acid synthesis and metabolism, as well as cancer development. Furthermore, these differential serum metabolites significantly affected 175 differential metabolites in soft palate tissue, mainly related to cancer development, signaling pathways, amino acid metabolism, nucleotide precursor or intermediate metabolism, respiratory processes, and disease. Importantly, CIH induction could significantly affect the expression of the cAMP pathway in soft palate tissue.ConclusionsOur findings suggest that targeting differential metabolites in serum and soft palate tissue may represent a new approach to clinical intervention and treatment of OSA simulated by the CIH.

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The Potential Effects of Aliskiren on Atrial Remodeling Induced by Chronic Intermittent Hypoxia in Rats.

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The Potential Effects of Aliskiren on Atrial Remodeling Induced by Chronic Intermittent Hypoxia in Rats.

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