Although increased predisposition to cardiac fibrosis and cardiac dysfunction has been demonstrated in the perinatally nicotine exposed heart, the underlying mechanisms remain unclear. Using a well-established rat model and cultured primary neonatal rat cardiac fibroblasts, the effect of perinatal nicotine exposure on offspring heart extracellular matrix deposition and the likely underlying mechanisms were investigated. Perinatal nicotine exposure resulted in increased collagen type I (COL1A1) and III (COL3A1) deposition along with a decrease in miR-29 family and an increase in long non-coding RNA myocardial infarction associated transcript (MIAT) levels in offspring heart. Nicotine treatment of isolated primary neonatal rat cardiac fibroblasts suggested that these effects were mediated via nicotinic acetylcholine receptors including α7 and the induced collagens accumulation was reversed by a gain-of function of miR-29 family. Knockdown of MIAT resulted in increased miR-29 family and decreased COL1A1 and COL3A1 levels, suggesting nicotine-mediated MIAT induction as the underlying mechanism for nicotine-induced collagen deposition. Luciferase reporter assay and RNA immunoprecipitation studies showed an intense physical interaction between MIAT, miR-29 family, and argonaute 2, corroborating the mechanistic link between perinatal nicotine exposure and increased extracellular matrix deposition. Overall, perinatal nicotine exposure resulted in lower miR-29 family levels in offspring heart, while it elevated cardiac MIAT and collagen type I and III levels. These findings provide mechanistic basis for cardiac dysfunction in perinatal nicotine exposed offspring and offer multiple novel potential therapeutic targets.

中文翻译：

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围产期尼古丁暴露后代心脏细胞外基质沉积增加的机制。

尽管在围产期暴露于尼古丁的心脏中已经证明心脏纤维化和心脏功能障碍的易感性增加，但其潜在机制仍不清楚。使用成熟的大鼠模型和培养的原代新生大鼠心脏成纤维细胞，研究了围产期尼古丁暴露对后代心脏细胞外基质沉积的影响以及可能的潜在机制。围产期尼古丁暴露导致 I 型胶原蛋白 (COL1A1) 和 III 型胶原蛋白 (COL3A1) 沉积增加，同时 miR-29 家族的减少和后代心脏中长链非编码 RNA 心肌梗死相关转录物 (MIAT) 水平的增加。尼古丁处理分离的原代新生大鼠心脏成纤维细胞表明这些作用是通过包括α7在内的烟碱型乙酰胆碱受体介导的，并且诱导的胶原蛋白积累被miR-29家族的功能获得逆转。MIAT 的敲除导致 miR-29 家族增加并降低 COL1A1 和 COL3A1 水平，表明尼古丁介导的 MIAT 诱导是尼古丁诱导的胶原沉积的潜在机制。荧光素酶报告基因检测和 RNA 免疫沉淀研究表明 MIAT、miR-29 家族和 argonaute 2 之间存在强烈的物理相互作用，证实了围产期尼古丁暴露与细胞外​​基质沉积增加之间的机制联系。总体而言，围产期尼古丁暴露导致后代心脏中 miR-29 家族水平降低，虽然它提高了心脏 MIAT 和 I 型和 III 型胶原蛋白的水平。这些发现为围产期尼古丁暴露后代的心脏功能障碍提供了机制基础，并提供了多种新的潜在治疗靶点。