Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Autor: Christian Jux, Maria Hennig, Saskia Fiedler, Jörg-Detlef Drenckhahn, Ludwig Thierfelder
Rok vydání: 2017
Předmět:
0301 basic medicine
cardiac growth
Physiology
Organogenesis
Myocardial Biology
Intrauterine growth restriction
Apoptosis
mTORC1
Ventricular Function
Left
Molecular Cardiology
Pregnancy
cardiac mass
Myocytes
Cardiac
Cardiac Output
Promoter Regions
Genetic
Original Research
Mice
Knockout
Fetal Growth Retardation
biology
Heart development
Ventricular Remodeling
Organ Size
heart development
Prenatal Exposure Delayed Effects
Homeobox Protein Nkx-2.5
Female
Cardiology and Cardiovascular Medicine
medicine.drug
Cardiac function curve
medicine.medical_specialty
Mice
129 Strain
intrauterine growth restriction
Lyases
Gestational Age
Mechanistic Target of Rapamycin Complex 1
03 medical and health sciences
Fetal Heart
Internal medicine
Developmental biology
medicine
Animals
Ventricular remodeling
Mechanistic target of rapamycin
Cell Size
Sirolimus
business.industry
medicine.disease
Myocardial Contraction
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
fetal programming
Animals
Newborn
Cardiovascular and Metabolic Diseases
biology.protein
cardiac function
mechanistic target of rapamycin
business
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (m TORC 1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of m TORC 1 in intrauterine growth restriction and prenatal heart growth. Methods and Results We inhibited m TORC 1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces m TORC 1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin‐treated neonates exhibit a 16% reduction in body weight compared with vehicle‐treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin‐ versus vehicle‐treated mice at birth. Although proliferation rates in neonatal rapamycin‐treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle‐treated neonates. Rapamycin‐treated mice exhibit postnatal catch‐up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal m TORC 1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling. Conclusions Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of m TORC 1 in perinatal cardiac growth.
Databáze: OpenAIRE
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