Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs.

Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH.

Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension.

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

Engaging basic scientists in translational research: identifying opportunities, overcoming obstacles.

This report is based on the Federation of American Societies for Experimental Biology's symposium, "Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles," held in Chevy Chase, MD, March 24-25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges.

Towards improving the care of children with pulmonary hypertension: The rationale for developing a Pediatric Pulmonary Hypertension Network.

Pulmonary hypertension (PH) and related pulmonary vascular diseases contribute to high morbidity and mortality and treatment options remain limited. Despite the availability of new drug therapies, the long-term outcomes of patients with severe PH remain poor. This may be especially true for many children with PH. Although most clinical studies have emphasized studies of adult patients, PH in pediatrics can be devastating and often contributes to poor outcomes in diverse clinical settings in newborns, infants and children. Unfortunately, studies that address the safety and efficacy of PH therapies in children are rare, as most pharmaceutical studies have focused on the adult population and only in patients with a fairly limited range of associated conditions. Thus, pediatric PH has been understudied and little is understood regarding the natural history, mechanisms of disease, and treatment of childhood PH. Limitations regarding current translational approaches to children with PH are partly due to the relatively small numbers of patients with PH associated with specific pediatric disorders at each center; the small number of well-established, multidisciplinary programs in pediatric PH; little communication between translational and clinician-scientists; and limited interactions between existing PH programs. There is clearly a need to develop clinical infrastructure to better define the natural history and course of pediatric PH, to develop new strategies to identify at-risk patients early in their course, and to establish novel approaches to diagnose, monitor disease progression and treat children with PH. This article discusses the rationale, goals and initial steps in the establishment of an interactive network of investigators, care providers and multidisciplinary teams from several pediatric PH centers.

Oxygen-dependent signaling in pulmonary vascular smooth muscle.

The pulmonary circulation constricts in response to acute hypoxia, which is reversible on reexposure to oxygen. On exposure to chronic hypoxia, in addition to vasoconstriction, the pulmonary vasculature undergoes remodeling, resulting in a sustained increase in pulmonary vascular resistance that is not immediately reversible. Hypoxic pulmonary vasoconstriction is physiological in the fetus, and there are many mechanisms by which the pulmonary vasculature relaxes at birth, principal among which is the acute increase in oxygen. Oxygen-induced signaling mechanisms, which result in pulmonary vascular relaxation at birth, and the mechanisms by which chronic hypoxia results in pulmonary vascular remodeling in the fetus and adult, are being investigated. Here, the roles of cGMP-dependent protein kinase in oxygen-mediated signaling in fetal pulmonary vascular smooth muscle and the effects of chronic hypoxia on ion channel activity and smooth muscle function such as contraction, growth, and gene expression were discussed.