Sex differences in pulmonary vascular control: focus on the nitric oxide pathway

Although the incidence of pulmonary hypertension is higher in females, the severity and prognosis of pulmonary vascular disease in both neonates and adults have been shown to be worse in male subjects. Studies of sex differences in pulmonary hypertension have mainly focused on the role of sex hormones. However, the contribution of sex differences in terms of vascular signaling pathways regulating pulmonary vascular function remains incompletely understood. Consequently, we investigated pulmonary vascular function of male and female swine in vivo, both at rest and during exercise, and in isolated small pulmonary arteries in vitro, with a particular focus on the NO-cGMP-PDE5 pathway. Pulmonary hemodynamics at rest and during exercise were virtually identical in male and female swine. Moreover, NO synthase inhibition resulted in a similar degree of pulmonary vasoconstriction in male and female swine. However, NO synthase inhibition blunted bradykinin-induced vasodilation in pulmonary small arteries to a greater extent in male than in female swine. PDE5 inhibition resulted in a similar degree of vasodilation in male and female swine at rest, while during exercise there was a trend towards a larger effect in male swine. In small pulmonary arteries, PDE5 inhibition failed to augment bradykinin-induced vasodilation in either sex. Finally, in the presence of NO synthase inhibition, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in female swine both in vivo and in vitro. In conclusion, the present study demonstrated significant sex differences in the regulation of pulmonary vascular tone, which may contribute to understanding sex differences in incidence, treatment response, and prognosis of pulmonary vascular disease

Predicting protective gene biomarker of acute coronary syndrome by the circRNA-associated competitive endogenous RNA regulatory network

Background: The mortality and disability rates of acute coronary syndrome (ACS) are quite high. Circular RNA (circRNA) is a competitive endogenous RNA (ceRNA) that plays an important role in the pathophysiology of ACS. Our goal is to screen circRNA-associated ceRNA networks for biomarker genes that are conducive to the diagnosis or exclusion of ACS, and better understand the pathology of the disease through the analysis of immune cells. Materials and methods: RNA expression profiles for circRNAs (GSE197137), miRNAs (GSE31568), and mRNAs (GSE95368) were obtained from the GEO database, and differentially expressed RNAs (DEcircRNAs, DEmiRNAs, and DEmRNAs) were identified. The circRNA-miRNA and miRNA-mRNA regulatory links were retrieved from the CircInteractome database and TargetScan databases, respectively. As a final step, a regulatory network has been designed for ceRNA. On the basis of the ceRNA network, hub mRNAs were verified by quantitative RT-PCR. Hub genes were validated using a third independent mRNA database GSE60993, and ROC curves were used to evaluate their diagnostic values. The correlation between hub genes and immune cells associated with ACS was then analyzed using single sample gene set enrichment analysis (ssGSEA). Results: A total of 17 DEcircRNAs, 229 DEmiRNAs, and 27 DEmRNAs were found, as well as 52 circRNA-miRNA pairings and 10 miRNA-mRNA pairings predicted. The ceRNA regulatory network (circRNA-miRNA-mRNA) was constructed, which included 2 circRNA (hsa_circ_0082319 and hsa_circ_0005654), 4 miRNA (hsa-miR-583, hsa-miR-661, hsa-miR-671-5p, hsa-miR-578), and 5 mRNA (XPNPEP1, UCHL1, DBNL, GPC6, and RAD51). The qRT-PCR analysis result showed that the XPNPEP1, UCHL1, GPC6 and RAD51 genes had a significantly decreased expression in ACS patients. Based on ROC curve analysis, we found that XPNPEP1 has important significance in preventing ACS occurrence and excluding ACS diagnosis. ACS immune infiltration analysis revealed significant correlations between the other 3 hub genes (UCHL1, GPC6, RAD51) and the immune cells (Eosinophils, T folliculars, Type 2 T helper cells, and Imumature dendritic cells). Conclusion: Our study constructed a circRNA-related ceRNA network in ACS. The XPNPEP1 gene could be a protective gene biomarker for ACS. The UCHL1, GPC6 and RAD51 genes were significantly correlated with immune cells in ACS

Oxidative injury of the pulmonary circulation in the perinatal period: Short- and long-term consequences for the human cardiopulmonary system

Development of the pulmonary circulation is a complex process with a spatial pattern that is tightly controlled. This process is vulnerable for disruption by various events in the prenatal and early postnatal periods. Disruption of normal pulmonary vascular development leads to abnormal structure and function of the lung vasculature, causing neonatal pulmonary vascular diseases. Premature babies are especially at risk of the development of these diseases, including persistent pulmonary hypertension and bronchopulmonary dysplasia. Reactive oxygen species play a key role in the pathogenesis of neonatal pulmonary vascular diseases and can be caused by hyperoxia, mechanical ventilation, hypoxia, and inflammation. Besides the well-established short-term consequences, exposure of the developing lung to injurious stimuli in the perinatal period, including oxidative stress, may also contribute to the development of pulmonary vascular diseases later in life, through so-called ‘‘fetal or perinatal programming.’’ Because of these long-term consequences, it is important to develop a follow-up program tailored to adolescent survivors of neonatal pulmonary vascular diseases, aimed at early detection of adult pulmonary vascular diseases, and thereby opening the possibility of early intervention and interfering with disease progression. This review focuses on pathophysiologic events in the perinatal period that have been shown to disrupt human normal pulmonary vascular development, leading to neonatal pulmonary vascular diseases that can extend even into adulthood. This knowledge may be particularly important for expremature adults who are at risk of the long-term consequences of pulmonary vascular diseases, thereby contributing disproportionately to the burden of adult cardiovascular disease in the future

Changes in the nitric oxide pathway of the pulmonary vasculature after exposure to hypoxia in swine model of neonatal pulmonary vascular disease

Neonatal pulmonary vascular disease (PVD) is increasingly recognized as a disease that complicates the cardiopulmonary adaptations after birth and predisposes to long-term cardiopulmonary disease. There is growing evidence that PVD is associated with disruptions in the nitric oxide (NO)-cGMP-phosphodiesterase 5 (PDE5) pathway. Examination of the functionality of different parts of this pathway is required for better understanding of the pathogenesis of neonatal PVD. For this purpose, the role of the NO-cGMP-PDE5 pathway in regulation of pulmonary vascular function was investigated in vivo, both at rest and during exercise, and in isolated pulmonary small arteries