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. 2021 Jan 19;22(2):931.
doi: 10.3390/ijms22020931.

Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

Jihyun Lee  1   2 , Yujin Jung  3 , Seo Won Jeong  3 , Ga Hee Jeong  2 , Gue Tae Moon  2 , Miri Kim  3
Affiliations

Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

Jihyun Lee et al. Int J Mol Sci. .

Abstract

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

Keywords: angiogenesis; hippo signaling; rosacea; transcription activator with a PDZ-binding motif (TAZ); yes-associated protein (YAP).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Skin samples from patients with rosacea showed high levels of yes-associated protein (YAP) and transcription activator with a PDZ-binding motif (TAZ), compared with samples from healthy volunteers. Original magnification, ×200; scale bar = 100 μm. (b) Immunostaining intensities were calculated with ImageJ software. * means data was significant (p < 0.05), and ns means nonsignificant.
Figure 2
Figure 2
The LL-37-induced rosacea-like mouse model. Representative photomicrographs of YAP- and TAZ-, hematoxylin and eosin (H&E)-, and vascular endothelial growth factor (VEGF)-stained skin sections. Original magnification, X200; scale bar = 100 μm.
Figure 3
Figure 3
Quantitative polymerase chain reaction (qPCR) analyses of VEGF mRNA expression. Data represent the means and SEMs of three independent experiments (n = 3 for the control group and n = 5–6 for the other groups). * p < 0.05 (control group vs. LL-37 group), ** p < 0.01 (LL-37 group vs. verteporfin (VP) and triamcinolone (TA) groups) (Mann–Whitney U test).
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