Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by pulmonary arteriolar remodeling. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of pulmonary hypertension (PH). Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1) 18 PAH subjects and 2) 8 subjects with PH secondary to idiopathic pulmonary fibrosis (IPF) and 3) 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-␤, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and ␤-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms. bone morphogenic protein receptor type II; estrogen; idiopathic pulmonary fibrosis; microarrays; mitogen-activated protein kinase; nitric oxide; platelet-derived growth factor PULMONARY ARTERIAL HYPERTENSION (PAH) is a disease characterized by elevated mean pulmonary arterial pressures (Ն25 mmHg at rest or Ն30 mmHg during exercise) (56) and subsequent right ventricular hypertrophy and failure. Vascular remodeling, manifested by excessive proliferation of vascular endothelium, smooth muscle cells, and fibroblasts, resulting in thickening of the walls of the pulmonary arterioles and formation of plexiform lesions, is the underlying cause of the increased vascular resistance (65). The mean survival time without treatment is ϳ2.8 yr, and the ratio of affected women to men is up to 3:1 (38, 46). PAH is termed idiopathic when sporadic, and familial in the 6% of cases with a positive family history. Both forms appear to share the same pathophysiological processes (16).Bone morphogenic protein (BMP) receptor type II (BMPR2) mutations, including exon duplications and deletions and gene

Paleoanthropological evidence indicates that modern humans reached South Asia in one of the first dispersals out of Africa, which were later followed by migrations from different parts of the world. The variation of 20 microsatellite and 38 binary polymorphisms on the non-recombining part of the uniparental, hapliod Y-chromosome was examined in 1434 male individual of 87 different populations of India to investigate various hypothesis of migration and peopling of South Asia Sub-continent. This study revealed a total of 24 paternal lineages, of which haplogroups H, R1a1, O2a and R2 portrayed for approximately 70% of the Indian Y-Chromosomes. The high NRY diversity value (0.893) and coalescence age of approx. 45-50 KYA for H and C haplogroups signified an early settlement of the subcontinent by modern humans. Haplogroup frequency and AMOVA results provide similar evidence in support of a common Pleistocene origin of Indian populations, with partial influence of Indo-European gene pool on the Indian society. The differential Y-chromosome and mt DNA pattern in the two Austric speakers of India signaled that an earlier male-mediated exodus from South East Asia largely involved the Austro-Asiatic tribes, while the Tibeto-Burman males migrated with females through two different routes; one from Burma most likely brought the Naga-Kuki-Chin language and O3e Y-chromosomes and the other from Himalayas, which carried the YAP lineages into northern regions of subcontinent. Based on distribution of Y-chromosome haplogroups (H, C, O2a, and R2) and deep coalescing time depths for these paternal lineages, we propose that the present day Dravidian speaking populations of South India are the descendants of earliest Pleistocene settlers while Austro-Asiatic speakers came from SE Asia in a later migration event.

Background: Analysis of human complete mitochondrial DNA sequences has largely contributed to resolve phylogenies and antiquity of different lineages belonging to the majorhaplogroups L, N and M (East-Asian lineages). In the absence of whole mtDNA sequence information of M lineages reported in India that exhibits highest diversity within the sub-continent, the present study was undertaken to provide a detailed analysis of this macrohaplogroup to precisely characterize and unravel the intricate phylogeny of the lineages and to establish the antiquity of M lineages in India.

BackgroundThe Ser358Leu mutation in TMEM43, encoding an inner nuclear membrane protein, has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). The pathogenetic mechanisms of this mutation are poorly understood.MethodsTo determine the frequency of TMEM43 mutations as a cause of ARVC, we screened 11 ARVC families for mutations in TMEM43 and five desmosomal genes previously implicated in the disease. Functional studies were performed in COS-7 cells transfected with wildtype, mutant, and 1:2 wildtype:mutant TMEM43 to determine the effect of the Ser358Leu mutation on the stability and cellular localization of TMEM43 and other nuclear envelope and desmosomal proteins, assessed by solubility assays and immunofluorescence imaging. mRNA expression was assessed of genes potentially affected by dysfunction of the nuclear lamina.ResultsThree novel mutations in previously documented desmosomal genes, but no mutations in TMEM43, were identified. COS-7 cells transfected with mutant TMEM43 exhibited no change in desmosomal stability. Stability and nuclear membrane localization of mutant TMEM43 and of lamin B and emerin were normal. Mutant TMEM43 did not alter the expression of genes located on chromosome 13, previously implicated in nuclear envelope protein mutations leading to skeletal muscular dystrophies.ConclusionsMutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. The pathogenetic role of TMEM43 mutations in ARVC remains uncertain.

Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O 2 • − ) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor-and serum-independent proliferation, upregulation of matrix genes, and increased O 2• − production compared with control cells. Histologic analysis of SCDassociated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an α1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in endstage SCD-associated PAH.