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ANG II modulation of cardiac growth and remodeling in immature fetal sheep
Journal article   Open access   Peer reviewed

ANG II modulation of cardiac growth and remodeling in immature fetal sheep

Jeremy Sandgren, Thomas D Scholz and Jeffrey L Segar
American journal of physiology. Regulatory, integrative and comparative physiology, Vol.308(11), pp.R965-R972
06/01/2015
DOI: 10.1152/ajpregu.00034.2015
PMCID: PMC4451391
PMID: 25810382
url
https://doi.org/10.1152/ajpregu.00034.2015View
Published (Version of record) Open Access

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.
 Antihypertensive Agents - pharmacology Hyperplasia Cyclin B1 - metabolism Nitroprusside - pharmacology Cell Enlargement - drug effects Time Factors Hypertension - chemically induced Cyclin-Dependent Kinase Inhibitor p21 - metabolism Hypertension - prevention & control Blood Pressure - drug effects Angiotensin II - toxicity Biomarkers - metabolism Vasodilator Agents - pharmacology Cell Size - drug effects Cardiomegaly - physiopathology Gestational Age Hypertension - physiopathology Fetal Heart - growth & development Animals Myocytes, Cardiac - drug effects Fetal Heart - drug effects Signal Transduction - drug effects Cell Differentiation - drug effects Myocytes, Cardiac - physiology Cardiomegaly - chemically induced Sheep Cell Proliferation - drug effects Cyclin E - metabolism Proliferating Cell Nuclear Antigen - metabolism Cardiomegaly - metabolism Mitogen-Activated Protein Kinases - metabolism

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