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Mechanism underlying increased cardiac extracellular matrix deposition in perinatal nicotine-exposed offspring
- Source :
- Am J Physiol Heart Circ Physiol
- Publication Year :
- 2020
- Publisher :
- American Physiological Society, 2020.
-
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.
- Subjects :
- 0301 basic medicine
Nicotine
medicine.medical_specialty
Heart Diseases
Physiology
Offspring
Cardiac fibrosis
Gestational Age
Collagen Type I
Rats, Sprague-Dawley
Extracellular matrix
03 medical and health sciences
0302 clinical medicine
Pregnancy
Physiology (medical)
Internal medicine
medicine
Animals
Nicotinic Agonists
Myocardial infarction
Cells, Cultured
Acetylcholine receptor
Gene knockdown
business.industry
Myocardium
Age Factors
Fibroblasts
medicine.disease
Fibrosis
Extracellular Matrix
Collagen Type I, alpha 1 Chain
MicroRNAs
Collagen Type III
030104 developmental biology
Nicotinic agonist
Endocrinology
Animals, Newborn
Prenatal Exposure Delayed Effects
030220 oncology & carcinogenesis
Female
RNA, Long Noncoding
Cardiology and Cardiovascular Medicine
business
Research Article
medicine.drug
Subjects
Details
- ISSN :
- 15221539 and 03636135
- Volume :
- 319
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Heart and Circulatory Physiology
- Accession number :
- edsair.doi.dedup.....a614fcc8b4a2dcecbabe7d560d21d7c1