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Prenatal lipopolysaccharide exposure programs cardiac fibrosis via dysregulating of connexin 43 in offspring rats
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DOI：10.3892/mmr.2026.13830.png)
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Abstract
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The present study investigated the role of connexin 43 (Cx43) in mediating prenatal inflammation-induced cardiac fibrosis in offspring, specifically exploring its dynamic regulation with autophagy and DNA methylation pathways. Pregnant Sprague-Dawley rats received intraperitoneal injections of saline (control) or lipopolysaccharide (LPS, 0.79 mg/kg) on gestational days 8, 10 and 12. Offspring were sacrificed at 8 and 16 weeks postpartum. Myocardial tissues were subjected to histopathological examination and molecular analysis. Prenatal LPS exposure consistently induced significant cardiac fibrosis in the offspring. Reverse transcription-quantitative PCR revealed that mRNA levels of Cx43, LC3 and DNA methyltransferase 1 (DNMT1) were markedly reduced at 8 weeks; however, they were elevated above control levels at 16 weeks. Western blotting revealed persistent suppression of Cx43 protein expression at both ages, whereas the LC3-II/I ratio and DNMT1 protein levels paralleled the biphasic mRNA trends. In vitro experiments using neonatal rat cardiac fibroblasts treated with LPS (10 & micro;g/ml, 24 h) confirmed Cx43 and LC3 downregulation and DNMT1 upregulation. Targeted pharmacological interventions were used to clarify these regulatory relationships. Cotreatment with the Cx43 gap junction inhibitor carbenoxolone (400 & micro;M) and LPS further suppressed Cx43, LC3 and DNMT1 expression. However, cotreatment with the Cx43 agonist all-trans retinoic acid (10 & micro;M) attenuated LPS-induced DNMT1 upregulation and LC3-II/I ratio suppression. These findings demonstrate that the functional state of Cx43 critically links fetal inflammatory insults to postnatal cardiac fibrogenesis by dynamically regulating interconnected autophagy and DNA methylation, establishing Cx43 as an upstream regulatory node in this pathogenic network.
Keywords:
intrauterine inflammation
connexin 43
cardiac fibrosis
autophagy
DNA methylation
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