406987

MIR204

MIRN204|miRNA204;microRNA 204;MIR204;microRNA 204

-

9q21.12

miscRNA

Count: MIR204; 406987

pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.

Over the past decade, the importance of non-coding RNA such as microRNA has been established in numerous processes that drive human pathogenesis. These crucial molecular regulators modulate networks of target gene transcripts that, in turn, orchestrate cellular phenotypes such as cell survival, differentiation, proliferation, and metabolism among others and thus affect cardiopulmonary vascular disease conditions. Many of these same pathophenotypes figure prominently in the complex pathogenesis of pulmonary hypertension, an enigmatic vascular disorder characterized by a histological panvasculopathy and driven by disparate upstream triggers such as hypoxia, inflammation, and bone morphogenetic protein signaling. Yet, the importance of just a few microRNAs in pulmonary hypertension has been recognized, and we are only beginning to understand the integrative functions of these molecules in this disease. By combining systems biology with traditional experimental approaches, more direct insight into the pleiotropy of microRNA should not only further reveal the spectrum of molecular pathways that cause pulmonary hypertension, but also offer novel and much needed diagnostic and therapeutic strategies.

OBJECTIVE: The epsilon gamma delta beta (epsilongammadeltabeta)-thalassemias are rare sporadic disorders caused by deletion of the beta-globin gene cluster. The main clinical feature is marked prenatal and neonatal anemia that resolves spontaneously within a few months. Reports originating mainly from Europe have so far identified 30 such deletions The aim of the present work was to describe a novel 1.78-Mb deletion, the longest ever reported, and to detail the clinical features in 12 members of an extended Bedouin family. METHODS: The deletion was identified by globin gene multiplex ligation-dependent probe amplification (MLPA) of the beta-globin cluster and further characterized by comparative genomic hybridization. Past and present clinical and laboratory data of ten symptomatic and two asymptomatic patients were collected. RESULTS: A 1.78-Mb epsilongammadeltabeta-deletion, the largest ever described, was identified in all patients. Although other genes were included in the deletion, no other symptoms were observed. Of the ten symptomatic fetuses and neonates, three died of the disease. The remainder required packed cell transfusions during the first months of life. Pregnancy complications included intrauterine growth restriction and oligohydramnios, as well as additional neonatal complications including prematurity and persistent pulmonary hypertension of the neonate. CONCLUSIONS: We suggest that epsilongammadeltabeta-thalassemia be added to the list of hemoglobinopathies that can cause neonatal anemia and that MLPA of the beta-globin cluster be used to confirm its diagnosis. Careful surveillance during pregnancy is important to reduce neonatal mortality and morbidity, especially given the dramatic improvement that occurs later.CI - (c) 2012 John Wiley & Sons A/S.