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Mechanism underlying increased cardiac extracellular matrix deposition in perinatal nicotine-exposed offspring
Tsai-Der Chuang1, Aamir Ansari2, Celia Yu2
1Department 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.
Insights
Perinatal nicotine exposure increases cardiac fibrosis by elevating MIAT levels and decreasing miR-29, leading to collagen deposition and potential heart dysfunction in offspring. These findings reveal new therapeutic targets for nicotine-induced heart damage.
Area of Science:
- Cardiovascular Biology
- Developmental Toxicology
- Molecular Cardiology
Background:
- Perinatal nicotine exposure is linked to cardiac fibrosis and dysfunction.
- The precise molecular mechanisms driving these cardiac changes remain largely unknown.
Purpose of the Study:
- To investigate the impact of perinatal nicotine exposure on cardiac extracellular matrix deposition.
- To elucidate the underlying molecular mechanisms, focusing on noncoding RNAs and collagen synthesis.
Main Methods:
- Utilized a rat model for perinatal nicotine exposure.
- Employed cultured primary neonatal rat cardiac fibroblasts for mechanistic studies.
- Assessed collagen type I (COL1A1) and III (COL3A1) levels, miR-29 family, and myocardial infarction-associated transcript (MIAT) expression.
- Performed knockdown and gain-of-function studies for MIAT and miR-29, respectively.
- Utilized luciferase reporter and RNA immunoprecipitation assays.
Main Results:
- Perinatal nicotine exposure increased COL1A1 and COL3A1 deposition in offspring hearts.
- Nicotine exposure decreased miR-29 family levels and increased MIAT levels.
- MIAT induction was identified as a key mechanism for nicotine-induced collagen accumulation.
- miR-29 family restoration reversed nicotine-induced collagen deposition.
- MIAT, miR-29 family, and argonaute 2 showed significant physical interaction.
Conclusions:
- Perinatal nicotine exposure disrupts cardiac extracellular matrix homeostasis via MIAT/miR-29 pathways.
- Elevated MIAT and reduced miR-29 contribute to cardiac fibrosis in offspring.
- These findings provide mechanistic insights into nicotine-induced cardiac dysfunction and identify potential therapeutic targets.
Abstract:
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.NEW & NOTEWORTHY 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.
