Gene expression in BMPR2 mutation carriers with and without evidence of Pulmonary Arterial Hypertension suggests pathways relevant to disease penetrance

<p>Abstract</p> <p>Background</p> <p>While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. This finding suggests that modifier genes contribute to FPAH clinical expression. Since modifiers are likely to be common alleles, this problem is not tractable by traditional genetic approaches. Furthermore, examination of gene expression is complicated by confounding effects attributable to drugs and the disease process itself.</p> <p>Methods</p> <p>To resolve these problems, B-cells were isolated, EBV-immortalized, and cultured from familial PAH patients with BMPR2 mutations, mutation positive but disease-free family members, and family members without mutation. This allows examination of differences in gene expression without drug or disease-related effects. These differences were assayed by Affymetrix array, with follow-up by quantitative RT-PCR and additional statistical analyses.</p> <p>Results</p> <p>By gene array, we found consistent alterations in multiple pathways with known relationship to PAH, including actin organization, immune function, calcium balance, growth, and apoptosis. Selected genes were verified by quantitative RT-PCR using a larger sample set. One of these, CYP1B1, had tenfold lower expression than control groups in female but not male PAH patients. Analysis of overrepresented gene ontology groups suggests that risk of disease correlates with alterations in pathways more strongly than with any specific gene within those pathways.</p> <p>Conclusion</p> <p>Disease status in BMPR2 mutation carriers was correlated with alterations in proliferation, GTP signaling, and stress response pathway expression. The estrogen metabolizing gene CYP1B1 is a strong candidate as a modifier gene in female PAH patients.</p

Crystal-field and Kondo-scale investigations of CeMIn5 (M=Co, Ir, and Rh): A combined x-ray absorption and inelastic neutron scattering study

Linear polarized soft-x ray absorption (XAS) and inelastic neutron scattering (INS) experiments have been performed on CeMIn5 with M = Rh, Ir, and Co to determine the crystal-field scheme and characteristic Kondo temperatures T* for the hybridization between 4f and conduction electrons. The ground state wave functions are determined from the polarization dependent soft-XAS data at the cerium M4,5 edge and the crystal-field splittings from INS. The characteristic temperature T* has been determined from the line widths of the neutron scattering data. We find that the quasielastic line widths of the superconducting compounds CeCoIn5 and CeIrIn5 are comparable with the low energy crystal-field splitting

Spectroscopic determination of crystal-field levels in CeRh(2)Si(2) and CeRu(2)Si(2) and of the 4f(0) contributions in CeM(2)Si(2) (M=Cu, Ru, Rh, Pd, and Au)

We have determined the ground statewave functions and crystal field level schemes of CeRh2Si2 andCeRu2Si2 using linear polarized soft x ray absorption spectroscopy XAS and inelastic neutron scattering. We find large crystal field splittings and ground state wave functions which are made of mainly Jz 5 2 gt; with some amount of amp; 8723;3 2 gt; in both the compounds. The 4f0 contribution to the ground state of several members of the CeM2Si2 family with M Cu, Ru, Rh, Pd, and Au has been determined with XAS, and the comparison reveals a trend concerning the delocalization of the f electrons. Absolute numbers are extracted from scaling to results from hard x ray photoelectron spectroscopy on CeRu2Si2 by Yano et al. [Phys. Rev. B 77, 035118 2008

The serotonin hypothesis of pulmonary hypertension revisited

The serotonin hypothesis of pulmonary arterial hypertension (PAH) arose after an outbreak of PAH in patients taking the anorexigenic drugs aminorex and dexfenfluramine. Both of these drugs are serotonin transporter (SERT) substrates and indirect serotinergic agonists. There is now a wealth of evidence to support a role for serotonin in the pathobiology of PAH. Synthesis of serotonin can occur in pulmonary artery endothelial cells by the enzyme tryptophan hydroxylase 1 (TPH1). Serotonin then acts at the 5-HT1B receptor and the SERT to mediate constriction and proliferation of pulmonary artery smooth muscle cells. Downstream signalling molecules which play a role in serotonin-induced constriction and proliferation include reactive oxygen species (ROS), Rho-kinase (ROCK) p38 and extracellular signal-regulated kinase (ERK). There is also evidence to suggest that serotonin may interact with the bone morphogenetic receptor type II (BMPRII) to provide a ‘second hit’ risk factor for PAH