Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene

Abstract

Research regarding understanding of the molecular mechanisms of pulmonary hypertension (PH) has experienced great progress in the last 3 yrs. Efforts to map the genetic susceptibility of familial primary pulmonary hypertension (FPPH) succeeded in localizing the gene site to the region 2q32-33, or so-called PPH1 gene site, which encompasses y3 centimorgan [1,2]. This finding raised the hope that important information could be generated since the prevailing concepts concerning the pathogenesis of primary pulmonary hypertension (PPH) have revolved around the pathophysiological roles of cellular components of vascular remodelling and abnormalities of pulmonary vascular tone control. The importance of the alterations of pulmonary vascular morphology was felt, by some, to be minimal, since they were interpreted to occur late in the disease process. Clearly, concepts were borrowed from hypoxic pulmonary vasoconstriction, yet severe PH is an irreversible disease with a magnitude of pulmonary hypertension not usually seen in acute or chronic hypoxia. Shortly after the FPPH locus had been announced, plexiform lesions in PPH were characterized to represent a tumour-like proliferation of a monoclonal population of endothelial cells, indicating that the endothelial cells arose from a selective growth of a single cell, whereas, in secondary PH, endothelial cells in plexiform lesions were polyclonal [3,4]. This finding in turn pointed towards mutational events, such as involving activation of growth-inducing kinase receptors or loss of tumour suppressor genes, as being responsible for the clonal expansion of endothelial cells in PPH [5].Recently, germline mutations in the bone morphogenetic protein receptor II (BMPR-II) (coded within the 2q32-33 region of the PPH1 gene site) were identified in a cohort of patients with FPPH [6,7] (fig. 1) and somatic losses of nucleotides in short stretches of repetitive mono-or dinucleotide sequences of the transforming growth factor-b receptor II (TGF-b RII) and Bax genes were found in endothelial cells in PPH, but not in secondary PH [9]. These findings lead to a novel hypothesis that germline and/or somatic mutations in key cell growth regulatory genes play a critical role in the development of idiopathic sporadic and familial PH. There is growing support of the concept that the dysregulation of endothelial cell growth in PPH has several fundamental properties in common with those seen in neoplastic processes.The present authors believe that these recent discoveries have opened a molecular/genetic perspective for research in severe PH. However, several important questions about how these findings relate to the mechanisms, the clinical presentation, and pulmonary haemodynamics of severe PH still remain unanswered.Bone morphogenetic protein receptor-II mutations in familial primary pulmonary hypertension: can they explain the disease process?Two groups almost simultaneously reported that BMP-RII mutations occur in a cohort of patients with FPPH [6,7]. BMPR-II mutations were identified in nin...

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Propylthiouracil Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

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