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MiR‑101a‑3p overexpression prevents acetylcholine‑CaCl₂‑induced atrial fibrillation in rats via reduction of atrial tissue fibrosis, involving inhibition of EZH2.

ABSTRACT: Atrial fibrillation (AF), a clinically common heart arrhythmia, can result in left ventricular hypofunction, embolism and infarction. MicroRNA (miR)‑101a‑3p is lowly expressed in atrial tissues of patients with AF, but its role in AF remains unknown. In the present study, an AF model in rats was established via intravenous injection of acetylcholine (Ach)‑CaCl₂. The downregulation of miR‑101a‑3p and upregulation of enhancer of zeste 2 homolog 2 (EZH2) were observed in AF model rats, indicating the involvement of miR‑101a‑3p and EZH2 in AF development. To study the effect of miR‑101a‑3p on AF in vivo, AF model rats were intramyocardially injected with lentivirus expressing miR‑101a‑3p. Electrocardiogram analysis identified that miR‑101a‑3p overexpression restored disappeared P wave and R‑R interphase changes in Ach‑CaCl₂‑induced rats. Overexpression of miR‑101a‑3p also increased the atrial effective refractory period, reduced AF incidence and shortened duration of AF. Histological changes in atrial tissues were observed after H&E and Masson staining, which demonstrated that miR‑101a‑3p reduced atrial remodeling and fibrosis in AF model rats. Moreover, EZH2 expression was downregulated in atrial tissues by miR‑101a‑3p induction. Immunohistochemistry for collagen Ⅰ and collagen III revealed a reduction in atrial collagen synthesis following miR‑101a‑3p overexpression in AF model rats. Additionally, miR‑101a‑3p lowered the expression of pro‑fibrotic biomarkers, including TGF‑β1, connective tissue growth factor, fibronectin and α‑smooth muscle actin. The luciferase reporter assay results also indicated that EZH2 was a target gene of miR‑101a‑3p. Taken together, it was found that miR‑101a‑3p prevented AF in rats possibly via inhibition of collagen synthesis and atrial fibrosis by targeting EZH2, which provided a potential target for preventing AF.

SUBMITTER: Zhu J

PROVIDER: S-EPMC8404104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Acetylcholine (ACh) shortens action potential duration (APD) in human atria. APD shortening facilitates atrial fibrillation (AF) by reducing the wavelength for reentry. However, the influence of ACh on electrical conduction in human atria and its contribution to AF are unclear, particularly when combined with impaired conduction from interstitial fibrosis. Objective:To investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches. Methods:S1S2 pacing (S1 = 600 ms and S2 = variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyte to quantify the effects of ACh on APD, maximum upstroke velocity (V max ), and resting membrane potential (RMP); a monolayer of LAA myocytes to quantify the effects of ACh on conduction; and 3) an intact left atrium (LA) to determine the effects of ACh on arrhythmogenicity. Heterogeneous ACh and interstitial fibrosis were applied to the monolayer and LA models. To corroborate the simulations, APD and RMP from isolated human atrial myocytes were recorded before and after 0.1 ?M ACh. At the tissue level, LAAs from AF patients were optically mapped ex vivo using Di-4-ANEPPS. The difference in total activation time (AT) was determined between AT initially recorded with S1 pacing, and AT recorded during subsequent S1 pacing without (n = 6) or with (n = 7) 100 ?M ACh. Results:In LAA myocyte simulations, S1 pacing with 0.1 ?M ACh shortened APD by 41 ms, hyperpolarized RMP by 7 mV, and increased V max by 27 mV/ms. In human atrial myocytes, 0.1 ?M ACh shortened APD by 48 ms, hyperpolarized RMP by 3 mV, and increased V max by 6 mV/ms. In LAA monolayer simulations, S1 pacing with ACh hyperpolarized RMP to delay total AT by 32 ms without and 35 ms with fibrosis. This led to unidirectional conduction block and sustained reentry in fibrotic LA with heterogeneous ACh during S2 pacing. In AF patient LAAs, S1 pacing with ACh increased total AT from 39.3 ± 26 ms to 71.4 ± 31.2 ms (p = 0.036) compared to no change without ACh (56.7 ± 29.3 ms to 50.0 ± 21.9 ms, p = 0.140). Conclusion:In fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry.

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MiR‑101a‑3p overexpression prevents acetylcholine‑CaCl₂‑induced atrial fibrillation in rats via reduction of atrial tissue fibrosis, involving inhibition of EZH2.

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MiR‑101a‑3p overexpression prevents acetylcholine‑CaCl2‑induced atrial fibrillation in rats via reduction of atrial tissue fibrosis, involving inhibition of EZH2.

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OmicsDI is part of the ELIXIR infrastructure

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MiR‑101a‑3p overexpression prevents acetylcholine‑CaCl₂‑induced atrial fibrillation in rats via reduction of atrial tissue fibrosis, involving inhibition of EZH2.