The Jagged-1/Notch1 Signaling Pathway Promotes the Construction of Tissue-Engineered Heart Valves.

Background: Tissue-engineered heart valves (TEHVs) are promising new heart valve substitutes for valvular heart disease. The Notch signaling pathway plays a critical role in the development of congenital heart valves. Objective: To investigate the role of the Notch signaling pathway in the construction of TEHVs. Methods: The induced endothelial cells, which act as seed cells, were differentiated from adipose-derived stem cells and were treated with Jagged-1 (JAG-1) protein and γ-secretase inhibitor (DAPT, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester), respectively. Cell phenotypic changes, the expression of proteins relating to the epithelial-mesenchymal transition (EMT), and changes in paxillin expression were detected. Decellularized valve scaffolds were produced from decellularized porcine aortic valves. The seed cells were them inoculated into Matrigel-coated flap scaffolds for complex culture and characterization. Results: JAG-1 significantly reduced apoptosis and promoted the seeded cells' proliferation and migration ability, in contrast to the treatment of DAPT. In addition, the expression of EMT-related proteins, E-cadherin and N-cadherin, was significantly increased after treatment with JAG-1 and was reduced after the application of DAPT. Meanwhile, the adhesive-related expression of paxillin and fibronectin proteins was increased after the activation of Notch1 signaling and vice versa. Of interest, activation of the Notch1 signaling pathway resulted in more closely arranged cells on the valve surface after recellularization. Conclusion: Activation of the JAG-1/Notch1 signaling pathway increased seeded cells' proliferation and migratory ability and promoted the EMT and adhesion of seed cells, which was conducive to binding to the matrix, facilitating accelerated endothelialization of TEHVs.

Analysis of the genetic contribution to thoracic aortic aneurysm or dissection in a prospective cohort of patients with familial and sporadic cases in East China.

BACKGROUND: Thoracic aortic aneurysm or dissections (TAADs) represent a group of life-threatening diseases. Genetic aetiology can affect the age of onset, clinical phenotype, and timing of intervention. We conducted a prospective trial to determine the prevalence of pathogenic variants in TAAD patients and to elucidate the traits related to harbouring the pathogenic variants. One hundred and one unrelated TAAD patients underwent genetic sequencing and analysis for 23 TAAD-associated genes using a targeted PCR and next-generation sequencing-based panel. RESULTS: A total of 47 variants were identified in 52 TAAD patients (51.5%), including 5 pathogenic, 1 likely pathogenic and 41 variants of uncertain significance. The pathogenic or likely pathogenic (P/LP) variants in 4 disease-causing genes were carried by 1 patient with familial and 5 patients with sporadic TAAD (5.9%). In addition to harbouring one variant causing familial TAAD, the FBN1 gene harboured half of the P/LP variants causing sporadic TAAD. Individuals with an age of onset less than 50 years or normotension had a significantly increased genetic risk. CONCLUSIONS: TAAD patients with a younger age at diagnosis or normotension were more likely to carry a P/LP variant; thus, routine genetic testing will be beneficial to a better prognosis through genetically personalized care prior to acute rupture or dissection.

Death-Associated Protein Kinase 1 Regulates Oxidative Stress in Cardiac Ischemia Reperfusion Injury.

To investigate the role of death-associated protein kinase 1 (DAPK1) in cardiac ischemia reperfusion (I/R) in vivo, and to determine whether the process is regulated by nuclear factor E2-associated factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (keap1). Western blot analysis was used to analyze the expression level of DAPK1 at different time points. The hemodynamic parameters and apoptosis of cardiac I/R injury in vivo were observed using DAPK1 knockdown lentivirus. The oxidative stress of I/R in vivo was observed. Nrf2-IN-1 was applied to determine whether the role of DAPK was regulated by Nrf2/keap1. Results show that the DAPK1 expression increased to a peak after 12 h of I/R. Moreover, the level of DAPK1 expression decreased, as determined by Western blot, after DAPK1 knockdown lentivirus administration. In addition, the hemodynamic parameters of the DAPK1-shRNA group were improved. The apoptosis level (Bax, Bcl-2, cleaved caspase-3, and TUNEL staining) increased in the I/R group, and the DAPK1 knockdown lentivirus could reverse the injury. The oxidative stress indices (CK, cTn-1, CAT, LDH, GSH-PX, MDA, and SOD) also improved in the DAPK1-shRNA group. Finally, Nrf2-IN-1 inhibited tNrf2, nNrf2, and Bcl-2 expression and boosted keap1, Bax, and cleaved caspase-3 expression after DAPK1 lentivirus administration. These findings suggest that DAPK1 may regulate the oxidative stress in cardiac I/R, and Nrf2/keap1 may be the downstream target factor of DAPK1.

Prenatal ultrasound diagnosis and management of fetal aortopulmonary septal defects: a case series.

BACKGROUND: To investigate the prenatal ultrasound diagnosis and management of patients with aortopulmonary septal defects (APSDs). METHODS: A total of 8 fetuses with APSDs who underwent fetal echocardiography at our hospital from January 2015 to January 2019 were retrospectively included in this study. RESULTS: Among the 8 fetuses, there were 4 cases of type I APSD, 3 cases were type II, and 1 case was type III. Among the 8 cases, there were 2 cases of simple APSD. There were echocardiographic characteristics that were common to all 3 types of APSD. This included defects between the ascending aorta and the trunk of the pulmonary artery in the short-axis section of the aorta, and in the three vessels and the three-vessel trachea section. Furthermore, the "V"-shaped structure confluence point of all APSD cases was positioned more forward than normal in the three-vessel trachea section. Type I APSD can be better characterized by the cross-section of the double outflow tract of the aorta and the pulmonary artery, which is close to the aortic valve and pulmonary valve. Type II APSD can be clearly diagnosed by the short-axis view of the aorta. Since the defect between the aorta and the pulmonary artery is distant from the aortic valve and pulmonary valve, the defect does not involve the bifurcation of the pulmonary artery and may be associated with an ectopic origin of the right pulmonary artery. Type III APSD is similar to a permanent arterial trunk, and the space between the ascending aorta and the trunk of the pulmonary artery is completely missing. Color and pulse Doppler showed shunt flow in the defects. CONCLUSIONS: APSD can be diagnosed and classified by fetal echocardiography. This, together with the presence or absence of fetal intracardiac and extracardiac deformities, can provide valuable prenatal information to pregnant women and their families, which may facilitate timely diagnosis and timely surgical treatment after birth.