title: ANG II modulation of cardiac growth and remodeling in immature fetal sheep.
abstract: ANG II increases fetal blood pressure and stimulates fetal heart growth; however, little is known regarding its direct effects on cardiomyocytes in vivo. We sought to determine whether ANG II stimulates heart growth and cardiomyocyte hypertrophy and/or hyperplasia in utero in the immature fetal heart independent of the effects on cardiac afterload. In twin gestation, fetal sheep at ∼100 days gestation (term 145 days), one fetus received a chronic (6 days) infusion of ANG II alone (50 μg·kg(-1)·min(-1)) or ANG II plus nitroprusside (NTP) to attenuate the increase in blood pressure; noninstrumented twins served as controls. ANG II alone, but not ANG II + NTP resulted in a significant increase in heart mass (left and right ventricle + septum, corrected for body weight) compared with controls. ANG II, but not ANG II+NTP, also significantly increased cardiomyocyte area compared with control and increased the percentage of binucleated myocytes. ANG II with or without concomitant infusion of NTP increased cardiac PCNA expression, a marker of proliferation. Steady-state protein expression of terminal mitogen-activated protein kinases, cyclin B1, cyclin E1, and p21 were similar among groups. We conclude that in vivo, ANG II increases fetal cardiac mass via cardiomyocyte hypertrophy, differentiation, and to a lesser extent hyperplasia. The effects of ANG II on hypertrophy appear dependent upon the increase in blood pressure (mechanical load), whereas effects on proliferation are load-independent.
authors: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Jeremy
authors: J
authors: Sandgren
authors: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Thomas D
authors: TD
authors: Scholz
authors: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa jeffrey-segar@uiowa.edu.
authors: Jeffrey L
authors: JL
authors: Segar
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects; D049108:Cell Enlargement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects*; D056744:Cyclin B1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005318:Fetal Heart / Q000187:drug effects* / Q000254:growth & development; D005865:Gestational Age; D006965:Hyperplasia; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D015415:Biomarkers; D056744:Cyclin B1; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D014665:Vasodilator Agents; D000804:Angiotensin II; D009599:Nitroprusside; D020928:Mitogen-Activated Protein Kinases
keywords: cardiomyocyte; heart; hyperplasia; hypertrophy