Rac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development

Leung, Carmen; Liu, Yin; Lu, Xiangru; Kim, Mella Y.; Drysdale, Thomas A.; Feng, Qingping

doi:10.1161/jaha.115.002508

Cited by 21 publications

(19 citation statements)

References 55 publications

(128 reference statements)

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“…We have recently shown that defects in SHF signaling results in thin myocardium, septal defects and OFT defects [23,33]. The defective SHF progenitor contribution may explain the majority of heart malformations in the OFT, cardiac septum and cardiac valves induced by pregestational diabetes.…”

Section: Discussionmentioning

confidence: 99%

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice

Engineer¹,

Saiyin²,

Lu³

et al. 2018

Preprint

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word count: 248Main text word count: 4,612Figures: 9; Tables: 1 Supplementary Table: 1; Supplementary Figure: 1References: 50All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/304006 doi: bioRxiv preprint first posted online Apr. 18, 2018; 2 ABSTRACT Aims: Tetrahydrobiopterin (BH4) is a co-factor of endothelial nitric oxide synthase (eNOS), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan®), an orally active synthetic form of BH4 on eNOS uncoupling and congenital heart defects (CHDs) induced by pregestational diabetes in mice.Methods: Adult female mice were induced to pregestational diabetes by streptozotocin and bred with normal males to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHDs were identified by histological analysis. Cell proliferation, eNOS dimerization and reactive oxygen species (ROS) production were assessed in the fetal heart. Results:Pregestational diabetes results in a spectrum of CHDs in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHDs from 59% to 27% and major abnormalities, such as atrioventricular septal defect and double outlet right ventricle were absent in the sapropterin treated group. Lineage tracing reveals that pregestational diabetes results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased eNOS dimerization and lowered ROS levels in the fetal heart.Conclusions: Sapropterin treatment in the diabetic mothers improves eNOS coupling, increases cell proliferation and prevents the development of CHDs in the offspring. Thus, sapropterin may have therapeutic potential in preventing CHDs in pregestational diabetes.

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Section: Discussionmentioning

confidence: 99%

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice

Engineer¹,

Saiyin²,

Lu³

et al. 2018

Preprint

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“…In our study population, 11.9% of patients had a history of myocardial infarction; we found that 53.6% of patients with old myocardial infarction were not taking the AAβ, which suggests that application of medicine for improving prognosis of myocardial infarction was still inadequate. A recent clinical research conducted by Liu et al [ 16 ] that focused on the use and trends of ACEI/ARB therapy in China over the past decade (2001–2011), after analyzing 102,003 patients, they found that one-third of Chinese AMI patients with Class I indications do not receive ACEI/ARB therapy during hospitalization, with little improvement in rates over time. The underutilization of ACEI/ARB therapy was also observed in our study.…”

Section: Discussionmentioning

confidence: 99%

Real-world use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/β-blocks in Chinese patients before acute myocardial infarction occurs: patient characteristics and hospital follow-up

et al. 2018

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BackgroundCurrent guidelines recommend angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin-receptor blockers (ARB) or β-blockers (β-B) for secondary prevention in patients after an acute myocardial infarction (AMI). However, there is limited data to evaluate ACEI/ARB/β-B (AAβ) used before AMI on major adverse cardiovascular events (MACE), in China patients.ObjectivesThis study sought to investigate whether AAβ treatment prior to AMI is associated with better hospital outcomes at the onset of AMI.MethodsA total of 2705 patients were selected from the Cardiovascular Center Beijing Friendship Hospital Database Bank, and divided into two groups on the basis of admission prescription: AAβ (n = 872) or no-AAβ (n = 1833). The study was also designed using propensity-score matching (226 AAβ treated patients vs 452 no-AAβ treated patients). The primary outcome was a composite of cardiac death and heart function and infarct size during hospitalization follow-up.ResultsThe mean follow-up period was about 8 days in MACE. The Cox model showed the two groups had similar risk of cardiac death. The in-hospital mortality was 3.36% (3.33% of AAβ users and 3.38% of nonusers, p = 0.94). In adjusted analysis, there was still no difference in in-hospital mortality between the two groups (3.54% vs 2.88%, p = 0.64). However, the AAβ treated patients were associated with better heart function and smaller infarct size than the no-AAβ treated patients.ConclusionsThe in-hospital MACE was similar between AAβ treated patients and no-AAβ treated patients. However, treatment with AAβ before AMI was associated with improved heart function and smaller infarct size.

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“…The SHF was initially described as a progenitor field for the cardiac OFT and a rich literature has established the requirement of anterior SHF contributions for OFT development [5, 10-19, 60-63]. More recently, the contribution of posterior SHF cardiac progenitors to the OFT and the future subpulmonary myocardium has been reported, however, the mechanistic requirement for this contribution is not well understood [45, 64-66].…”

Section: Discussionmentioning

confidence: 99%

Gata4 drives Hh-signaling for second heart field migration and outflow tract development

Liu

Cheng

Xiang

et al. 2018

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32Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), cause 33 outflow tract (OFT) defects in both human and mouse. We investigated the molecular 34 mechanism underlying this requirement. Gata4 happloinsufficiency in mice caused OFT 35 defects including double outlet right ventricle (DORV) and conal ventricular septum 36 defects (VSDs). We found that Gata4 is required within Hedgehog (Hh)-receiving second 37 heart field (SHF) progenitors for normal OFT alignment. Increased Pten-mediated cell-38 cycle transition, rescued atrial septal defects but not OFT defects in Gata4 heterozygotes. 39 SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion in Gata4 40 heterozygote embryos. We find that Hh signaling and Gata4 genetically interact for OFT 41 development. Gata4 and Smo double heterozygotes displayed more severe OFT 42 abnormalities including persistent truncus arteriosus (PTA) whereas restoration of 43 Hedgehog signaling rescued OFT defects in Gata4-mutant mice. In addition, enhanced 44 expression of the Gata6 was observed in the SHF of the Gata4 heterozygotes. These 45 results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling 46 for OFT development. This study indicates that Gata4 potentiation of Hh signaling is a 47 general feature of Gata4-mediated cardiac morphogenesis and provides a model for the 48 molecular basis of CHD caused by dominant transcription factor mutations.49 3 50Gata4 is an important protein that controls the development of the heart. Human who 52 possess a single copy of Gata4 mutation display congenital heart defects (CHD), 53 including the double outlet right ventricle (DORV). DORV is an alignment problem in 54 which both the Aorta and Pulmonary Artery originate from the right ventricle, instead of 55 originating from the left and the right ventricles, respectively. To study how Gata4 56 mutation causes DORV, we used a Gata4 mutant mouse model, which displays DORV. 57We showed that Gata4 is required in the cardiac precursor cells for the normal alignment 58 of the great arteries. Although Gata4 mutation inhibits the rapid increase in number of the 59 cardiac precursor cells, rescuing this defects does not recover the normal alignment of 60 the great arteries. In addition, there is a movement problem of the cardiac precursor cells 61 when migrating toward the great arteries during development. We further showed that a 62 specific molecular signaling, Hh-signaling, is responsible to the Gata4 action in the 63 cardiac precursor cells. Importantly, over-activating the Hh-signaling rescues the DORV 64 in the Gata4 mutant embryos. This study provides an explanation for the ontogeny of 65 CHD. 66 4 67 Introduction 68 Congenital Heart Defects (CHDs) CHDs occurr in approximately 1% of live births [1] 69 and are the most common serious birth defects in humans [2, 3]. Approximately one third 70 of the CHDs involve malformations of the outflow tract (OFT), which leads to significant 71 morbidity and mortality o...

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Rac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development

Cited by 21 publications

References 55 publications

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice

Real-world use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/β-blocks in Chinese patients before acute myocardial infarction occurs: patient characteristics and hospital follow-up

Gata4 drives Hh-signaling for second heart field migration and outflow tract development

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