title: Increased cardiac workload by closure of the ductus arteriosus leads to hypertrophy and apoptosis rather than to hyperplasia in the late fetal period.
abstract: It is generally thought that adult mammalian cardiomyocytes compensate for an increased workload by hypertrophy, whereas fetal myocardium grows by cellular proliferation. We analyzed the response of late-fetal rat hearts upon an increased workload imposed by premature constriction of the ductus arteriosus with indomethacin. Initially the fetal heart responds by proliferative growth, as both wet weight and labeling index (bromodeoxyuridine incorporation) of the ventricles increased, whereas neither a change in the fibroblast fraction, ploidy and nucleation in the ventricles is observed. However, this hyperplastic growth is abrogated by a subsequent burst in apoptosis and followed by a hypertrophic response as based on a decrease in DNA and increase in both RNA and protein concentration. This hypertrophic growth was accompanied by a 1.4-fold increase in the volume of the cardiomyocytes. Changes in the molecular phenotype characteristic of pressure-overload hypertrophic growth accompany the process. Thus, the levels of expression of beta-myosin heavy chain and atrial natriuretic factor mRNA increased, of sarcoplasmic/endoplasmic reticulum ATPase (SERCA2) mRNA decreased, and of alpha-myosin heavy chain, phospholamban, and calsequestrin mRNA did not change. In situ hybridization showed that the pattern of mRNA expression changed first in the right ventricular wall and subsequently in the left ventricular free wall as well. It is concluded that pressure-overload imposed on the late-fetal heart induces limited proliferative growth complemented by extensive hypertrophic growth.
authors.affiliation: Experimental and Molecular Cardiology Group, Department of Anatomy and Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. m.j.vandenHoff@amc.uva.nl
authors.forename: Maurice J B
authors.initials: MJ
authors.lastname: van den Hoff
authors.forename: Ronald H Lekanne
authors.initials: RH
authors.lastname: Deprez
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ruijter
authors.forename: Piet A J
authors.initials: PA
authors.lastname: de Boer
authors.forename: Sabina
authors.initials: S
authors.lastname: Tesink-Taekema
authors.forename: Anita A
authors.initials: AA
authors.lastname: Buffing
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis; D001835:Body Weight; D001973:Bromodeoxyuridine / Q000494:pharmacology; D016923:Cell Death; D003251:Constriction, Pathologic / Q000139:chemically induced; D004373:Ductus Arteriosus / Q000473:pathology*; D005318:Fetal Heart / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental; D006965:Hyperplasia; D006984:Hypertrophy / Q000209:etiology*; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007213:Indomethacin / Q000633:toxicity; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D007213:Indomethacin