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. 2017 Mar 14;12(1):25.
doi: 10.1186/s13000-017-0614-7.

Implication of overexpression of dishevelled-associated activator of morphogenesis 1 (Daam-1) for the pathogenesis of human Idiopathic Pulmonary Arterial Hypertension (IPAH)

Shun Yanai  1 , Megumi Wakayama  2 , Haruo Nakayama  3 , Minoru Shinozaki  4 , Hisayuki Tsukuma  5 , Naobumi Tochigi  4 , Tetsuo Nemoto  4 , Tsutomu Saji  6 , Kazutoshi Shibuya  4
Affiliations

Implication of overexpression of dishevelled-associated activator of morphogenesis 1 (Daam-1) for the pathogenesis of human Idiopathic Pulmonary Arterial Hypertension (IPAH)

Shun Yanai et al. Diagn Pathol. .

Abstract

Background: Idiopathic 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.

Methods: We 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.

Results: Varying 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.

Conclusions: High Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.

Keywords: Daam-1; IPAH; Overexpression; Smooth muscle cells; Wnt/PCP pathway.

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Figures

Fig. 1
Fig. 1
Photomicrographs of anti–Wnt-11 antibody immunostaining. a Control: positive reactivity is confirmed in parietal cells of gastric fundic glands. b IPAH, PA: positive reactivity is not confirmed in endothelial cells, myofibroblasts, or SMC. c APAH, PA: positive reactivity is not confirmed in endothelial cells, myofibroblasts, or SMC. d Age-matched control, PA: positive reactivity is not confirmed in endothelial cells, myofibroblasts, or SMC
Fig. 2
Fig. 2
Photomicrographs of anti–Dvl-2 antibody immunostaining. a Built-in control: positive reactivity is confirmed in bronchial epithelial cells. b IPAH, PA: positive reactivity is confirmed in endothelial cells and SMC. c APAH, PA: positive reactivity is confirmed in endothelial cells and SMC. d Age-matched control, PA: positive reactivity is confirmed in endothelial cells and SMC
Fig. 3
Fig. 3
Photomicrographs of anti–Daam-1 antibody immunostaining. a Built-in control: positive reactivity is confirmed in bronchial epithelial cells. b IPAH, PA: positive reactivity is confirmed in endothelial cells, and SMC. c APAH, PA: positive reactivity is observed in endothelial cells and SMC. d Age-matched control, PA: positive reactivity is observed in endothelial cells and SMC
Fig. 4
Fig. 4
Positive expression rates of Dvl-2 and Daam-1 in pulmonary arteries from autopsy cases. a, Small arteries. b, Medium-sized arteries. * P < 0.05
Fig. 5
Fig. 5
Ratio of positive expression rates (Daam-1/Dvl-2)
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