Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension

Abstract

Primary pulmonary hypertension (PPH) is a disease of unknown etiology characterized by lumen-obliterating endothelial cell proliferation and vascular smooth muscle hypertrophy of the small precapillary pulmonary arteries. Because the vascular lesions are homogeneously distributed throughout the entire lung, we propose that a tissue fragment of the lung is representative of the whole lung. RNA extracted from the fragments is likely to provide meaningful information regarding the changes in gene expression pattern in PPH when compared with structurally normal lung tissue. We hypothesize that the lung tissue gene expression pattern of patients with PPH has a characteristic profile when compared with the gene expression pattern of structurally normal lungs and that this characteristic gene expression profile provides new insights into the pathobiology of PPH. Using oligonucleotide microarray technology, we characterized the expression pattern in the lung tissue obtained from 6 patients with primary pulmonary hypertension (PPH)-including 2 patients with the familial form of PPH (FPPH)-and from 6 patients with histologically normal lungs. For the data analysis, gene clusters were generated and the gene expression pattern differences between PPH and normal lung tissue and between PPH and FPPH lung tissue were compared. All PPH lung tissue samples showed a decreased expression of genes encoding several kinases and phosphatases, whereas several oncogenes and genes coding for ion channel proteins were upregulated in their expression. Importantly, we could distinguish by pattern comparison between sporadic PPH and FPPH, because alterations in the expression of transforming growth factor-beta receptor III, bone morphogenic protein 2, mitogen-activated protein kinase kinase 5, RACK 1, apolipoprotein C-III, and the gene encoding the laminin receptor 1 were only found in the samples from patients with sporadic PPH, but not in FPPH samples. We conclude that the microarray gene expression technique is a new and useful molecular tool that provides novel information pertinent to a better characterization and understanding of the pathobiology of the distinct clinical phenotypes of pulmonary hypertension.

Divergent Effects of BMP-2 on Gene Expression in Pulmonary Artery Smooth Muscle Cells From Normal Subjects and Patients With Idiopathic Pulmonary Arterial Hypertension

“…The data indicate that the bulk of the genes have markedly different expression levels between normal and IPAH PASMC. Among the genes whose expression levels are strongly correlated negatively (r < −0.9) or positively (r > +0.9) to the PAP, several are consistent with the report by Geraci et al [29]. For example, the expression levels of IP 3 receptors, Cl -channels, caveolin and Myc are much greater, whereas expression levels of BMPs, voltage-gated Na + and K + channels, mitochondrial outer membrane protein, mitochondrial citrate transport protein, and calcineurin are much less in IPAH PASMC than in normal PASMC.…”

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

“…[29][30][31][32][33][34] "Oxidant stress" has been reported in PAH by Cracowski et al, 35 who described increased isoprostane urinary levels that correlated with worsened patient survival. Further, using oligonucleotide microarray gene expression, Geraci et al 36 have described an increase in pulmonary expression of oxidative genes in PAH patients.…”

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

“…A microarray study in lung tissues from patients with idiopathic and familial pulmonary arterial hypertension showed increased mRNA expression of the voltage gated Na + channel β1 subunit [45]. The physiological significance of increased Na + currents in proliferating cells remains a mystery.…”