Abstract
BackgroundIdiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. Evidence from our recent study suggests that IPAH pathogenesis is related to upregulation of the Wnt/planar cell polarity (Wnt/PCP) pathway. We used microscopic observation and immunohistochemical techniques to identify expression patterns of cascading proteins—namely Wnt-11, dishevelled-2 (Dvl-2), and dishevelled-associated activator of morphogenesis 1 (Daam-1)—in pulmonary arteries.MethodsWe analyzed sections of formalin-fixed and paraffin-embedded autopsied lung tissues obtained from 9 IPAH cases, 7 associated pulmonary arterial hypertension cases, and 16 age-matched controls without pulmonary arterial abnormalities. Results of microscopic observation were analyzed in relation to the cellular components and size of pulmonary arteries.ResultsVarying rates of positive reactivity to Dvl-2 and Daam-1 were confirmed in all cellular components of pulmonary arteries, namely, endothelial cells, myofibroblasts, and medial smooth muscle cells. In contrast, none of these components was reactive to Wnt-11. No specific expression patterns were observed for endothelial cells or myofibroblasts under any experimental conditions. However, marked expression of Dvl-2 and Daam-1 was confirmed in smooth muscle cells. In addition, Dvl-2 was depleted while Daam-1 expression was elevated in IPAH, in contrast with specimens from associated pulmonary arterial hypertension cases and controls.ConclusionsHigh Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.
Highlights
Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis
Because Wnt-11 was not observed in any pulmonary arteries (PA) specimen but was confirmed in parietal cells of gastric fundic glands, our evaluation focused on the expression patterns for Dvl-2 and dishevelled-associated activator of morphogenesis 1 (Daam-1)
Daam-1 gene located on 14q23.1 in an aborted fetus with double-outlet right ventricle [45,46,47,48,49]. These findings suggest that Wnt-11, Dvl-2, and Daam-1 are a set of cascading proteins in the Wnt/planar cell polarity (Wnt/PCP) signal transduction pathway, which cannot be replaced by another signal transduction pathway
Summary
Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. The first autopsy case was described by Romberg in 1891, the cause of idiopathic pulmonary arterial hypertension (IPAH) is unknown [1]. The recent development of During the past decade, several studies have investigated the pathogenesis of IPAH, mutations in bone morphogenetic protein receptor II (BMPR2), a transforming growth factor β (TGFβ) superfamily. Only 20% of BMPR2-positive individuals develop IPAH during their lifetime and the male:female ratio of patients is 1:2.5. These findings complicate IPAH pathogenesis, and progress in treatment has been slow [5, 6]
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