The Effects of Angiotensin II and Specific Angiotensin Receptor Blockers on Embryonic Cardiac Development and Looping Patterns

Price, Robert L.; Carver, Wayne; Simpson, David G.; Fu, Lei; Zhao, Jinchuan; Borg, Thomas K.; Terracio, Louis

doi:10.1006/dbio.1997.8764

Cited by 53 publications

(32 citation statements)

References 57 publications

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“…The timing of the switch between AT2 and AT1 receptor predominance in fetal/neonatal heart may indicate a key stage of cardiac development susceptible to perturbations by unfavorable neonatal conditions. The latter is corroborated by studies showing that prenatal and early postnatal treatment with AT1 blockers and ACE inhibitors is associated with cardiac 22 and kidney 23,24 abnormal development. Cardiac hypertrophy and fibrosis and changes in Ang receptors have been reported in late fetal or young offspring subjected to deleterious fetal conditions [25][26][27] To our knowledge, no study beside our previous one 13 has reported cardiac expression of Ang receptors after neonatal hyperoxic exposure or other conditions associated with preterm infant environment.…”

Section: April 2016mentioning

confidence: 74%

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

et al. 2016

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R enin-angiotensin system (RAS) is a key component of cardiovascular and renal system homeostasis. RAS activation during development is well described 1 and contributes to organogenesis and growth, especially in the cardiovascular and renal systems. Among RAS components, angiotensin (Ang) II is the major peptide acting during fetal and neonatal life. Both subtypes of Ang receptors are expressed during fetal development 2,3 but have different patterns of expression during the fetal-neonatal transition. In rats, Ang type 2 (AT2) receptors are upregulated in the heart, large vessels, lungs, and kidneys during fetal development and progressively decline after birth, suggesting their contribution to fetal organogenesis. Ang type 1 (AT1) receptors, on the other hand, are detected late in fetal development, increase soon after birth, and are considered to contribute mainly to tissue maturation, growth, and postnatal adaptation. [2][3][4] This switching pattern of Ang receptors suggests that modifications of AT1/AT2 balance play a key role in different developmental stages. A disruption of this balance, depending on the stage of development, may negatively affect cardiovascular and renal homeostasis and contribute to the establishment of cardiovascular diseases.Deleterious perinatal conditions, including preeclampsia, intrauterine growth restriction, and preterm birth can lead to developmental programming of cardiovascular risk factors and diseases. 5,6 Preterm-born individuals in particular, whose numbers are growing in the population because of recent Abstract-Newborn rats exposed to high oxygen (O 2 ), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O 2 -exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O 2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O 2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O 2 exposure), P5, P10 (end of O 2 ), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O 2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O 2 -exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway...

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Section: April 2016mentioning

confidence: 74%

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

et al. 2016

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“…We know from the literature that apoptosis participates in the intrauterus and early postgestational heart development 14,15 and that all the components of the renin-angiotensin system are expressed by the fetal heart and participate in its normal development. 16,17 Interestingly, a recent study from a coauthor of this article showed that the 3 Shc isoforms are activated in the human fetal heart, in a period that is characterized by apoptotic and proliferative processes. 15 In our opinion, the p66 Shc knock-out may interfere with the heart development by inhibiting the apoptotic and hypertrophic signaling emanating from AT 1 or other factors as well as enhancing the proliferation of cardiomyocyte and CPCs.…”

Section: Shc Isoformsmentioning

confidence: 98%

Genetic Deletion of the p66 ^Shc Adaptor Protein Protects From Angiotensin II–Induced Myocardial Damage

et al. 2005

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Abstract-Angiotensin II (Ang II), acting through its G protein-coupled AT 1 receptor (AT 1 ), contributes to the precocious heart senescence typical of patients with hypertension, atherosclerosis, and diabetes. AT 1 was suggested to transactivate an intracellular signaling controlled by growth factors and their tyrosin-kinase receptors. In cultured vascular smooth muscle cells, this downstream mechanism comprises the p66 Shc adaptor protein, previously recognized to play a role in vascular cell senescence and death. The aim of the present study was 2-fold: (1)

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“…26 However, persistent upregulation of AT1 receptors later in life can lead to myocardial hypertrophy and changes in contractility. 27 In our study, upregulation of AT1 receptors could contribute to the development of cardiac remodeling and to cardiac compensating/decompensating responses during Ang II infusion in O 2 -exposed rats.…”

Section: 24mentioning

confidence: 99%

Transient Neonatal High Oxygen Exposure Leads to Early Adult Cardiac Dysfunction, Remodeling, and Activation of the Renin–Angiotensin System

et al. 2014

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Abstract-Perinatal conditions (such as preterm birth) can affect adult health and disease, particularly the cardiovascular system. Transient neonatal high O 2 exposure in rat in adulthood (a model of preterm birth-related complications) leads to elevated blood pressure, vascular rigidity, and dysfunction with renin-angiotensin system activation. We postulate that neonatal hyperoxic stress also affects myocardial structure, function, and expression of renin-angiotensin system components. Sprague-Dawley pups were kept with their mother in 80% O 2 or in room air (control) from days 3 to 10 of life. Left ventricular function was assessed in 4-, 7-, 12-week-old (echocardiography) and in 16-week-old (intraventricular catheterization) male O 2 -exposed versus control rats. At 16 weeks, hearts from O 2 -exposed rats showed cardiomyocyte hypertrophy, enhanced fibrosis, and increased expression of transforming growth factor-β1, senescence-associated proteins p53 and Rb, upregulation of angiotensin II type 1 (AT1) receptor expression (protein and AT1a/b mRNA), and downregulation of AT2 receptors. At 4 weeks (before blood pressure increase), the expression of cardiomyocyte surface area, fibrosis, p53, and AT1b was significantly increased and AT2 decreased in O 2 -exposed animals. After 4 weeks of continuous angiotensin II infusion (starting at 12 weeks), O 2 -exposed rats developed severe heart failure, with impaired myocardial mechanical properties compared with saline-infused rats. Transient neonatal O 2 exposure in rats leads to left ventricular hypertrophy, fibrosis and dysfunction, and increased susceptibility to heart failure under pressure overload. These results are relevant to the growing population of individuals born preterm who may be at higher risk of cardiac dysfunction when faced with increased peripheral resistance associated with hypertension, vascular diseases, and In cardiovascular disease, RAS plays a major role in vascular dysfunction, cardiac hypertrophy, and fibrosis through Ang II acting predominantly on its type I receptor (AT1) 10,11 triggering downstream mechanisms such as the profibrotics transforming growth factor-β1 (TGF-β1) and hypoxic-inducible factor-1α (HIF-1α), 12 as well as senescence-associated pathways. 13Activation of the RAS in the kidneys, brain, and systemic vasculature plays a key role in the elevation and maintenance of BP in experimental models associated with deleterious perinatal conditions including transient neonatal high O 2 exposure. 6,14 However, the effect of neonatal pro-oxidant conditions on cardiac RAS components has not been reported. To determine whether neonatal hyperoxia exposure impaired cardiac development and predisposed to cardiac dysfunction, myocardial structure, and function, expression of cardiac RAS components, as well as TGF-β1, HIF-1α, and senescenceassociated proteins, was determined in young, 4-week-old, and adult, 16-week-old rats infused or not with Ang II. Materials and MethodsSprague-Dawley pups were kept with their mother in 80% O 2 using an oxyc...

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The Effects of Angiotensin II and Specific Angiotensin Receptor Blockers on Embryonic Cardiac Development and Looping Patterns

Cited by 53 publications

References 57 publications

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

Genetic Deletion of the p66 ^Shc Adaptor Protein Protects From Angiotensin II–Induced Myocardial Damage

Transient Neonatal High Oxygen Exposure Leads to Early Adult Cardiac Dysfunction, Remodeling, and Activation of the Renin–Angiotensin System

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The Effects of Angiotensin II and Specific Angiotensin Receptor Blockers on Embryonic Cardiac Development and Looping Patterns

Cited by 53 publications

References 57 publications

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

Genetic Deletion of the p66 Shc Adaptor Protein Protects From Angiotensin II–Induced Myocardial Damage

Transient Neonatal High Oxygen Exposure Leads to Early Adult Cardiac Dysfunction, Remodeling, and Activation of the Renin–Angiotensin System

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Genetic Deletion of the p66 ^Shc Adaptor Protein Protects From Angiotensin II–Induced Myocardial Damage