Department of and Obstetrics, Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California.
Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California.
Am J Physiol Heart Circ Physiol. 2020 Sep 1;319(3):H651-H660. doi: 10.1152/ajpheart.00021.2020. Epub 2020 Aug 14.
Although increased predisposition to cardiac fibrosis and cardiac dysfunction has been demonstrated in the perinatally nicotine-exposed heart, the underlying mechanisms remain unclear. With the use of 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 noncoding 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. Using an established rat model and cultured primary neonatal cardiac fibroblasts, we show that nicotine mediated MIAT induction as the underlying mechanism for the excessive cardiac collagen deposition. These observations provide mechanistic basis for the increased predisposition to cardiac dysfunction following perinatal cigarette/nicotine exposure and offer novel potential therapeutic targets.
尽管围产期暴露于尼古丁会导致心脏纤维化和心功能障碍的倾向增加，但潜在机制仍不清楚。本研究使用成熟的大鼠模型和培养的原代新生大鼠心肌成纤维细胞，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及其潜在机制。围产期尼古丁暴露导致后代心脏中胶原 I 型 (COL1A1) 和 III 型 (COL3A1) 沉积增加，miR-29 家族水平降低，长链非编码 RNA 心肌梗死相关转录物 (MIAT) 水平升高。尼古丁处理分离的原代新生大鼠心肌成纤维细胞表明，这些作用是通过烟碱型乙酰胆碱受体（包括 α7 受体）介导的，诱导的胶原积累可被 miR-29 家族的功能获得逆转。MIAT 的敲低导致 miR-29 家族增加，COL1A1 和 COL3A1 水平降低，提示尼古丁介导的 MIAT 诱导是尼古丁诱导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。总的来说，围产期尼古丁暴露导致后代心脏中 miR-29 家族水平降低，而心脏 MIAT 和胶原 I 型和 III 型水平升高。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，并提供了多个潜在的治疗靶点。本研究使用成熟的大鼠模型和培养的原代新生大鼠心肌成纤维细胞，表明尼古丁介导的 MIAT 诱导是心脏胶原过度沉积的潜在机制。这些观察结果为围产期吸烟/尼古丁暴露后心脏功能障碍易感性增加提供了机制基础，并提供了新的潜在治疗靶点。
