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Author Topic: Verteporfin inhibits gene expression associated with fibrosis  (Read 889 times)

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Verteporfin inhibits gene expression associated with fibrosis
« on: December 28, 2018, 05:35:47 AM »

Verteporfin is a small molecule that by deactivates transcription in the Hippo-Yes Activated Protein (YAP) pathway, and is an FDA-approved macular degeneration drug. In vitro, verteporfin " ... blocked the expression of genes related to fibrosis in the YAP cascade in myofibroblasts derived from Peyronies Disease plaque." Actual Peyronie's plaque myofibroblasts, rather than plaques from an animal model.

Very interesting.

" ... our study shows that in vitro exposure of VP to (myo)fibroblasts inhibits the pathologic processes by means of the down-regulation of fibrosis-associated genes. Fibrosis is characterized by excessive production, deposition, and contraction of extracellular matrix (ECM), leading to significant organ dysfunction.11 Here we show that VP is able to reduce the expression of the 2 major fibrillary collagens, that is, collagen type I and type V, and the ECM component fibronectin (EDA-FN). This should lead to a less-excessive deposition of ECM. It also helps that VP is able to decrease SERPINH1 levels (also known as HSP47), a chaperone needed for the proper transportation of collagen. In fibrosis the ECM stiffens, even before scarring occurs, owing to an increased expression of enzymes involved in collagen cross-linking. In our study we found that the expression of at least 2 of these enzymes, LOXL2 and PLOD2, is inhibited by VP. This should lead to a less-stiff ECM. In addition, collagen cross-linked by hydroxylysine residues mediated by PLOD2 is more difficult to degrade by matrix metalloproteinases.12 Lower cross-links levels derived from PLOD2 most likely results in a faster degradation of collagen molecules, resulting in less ECM accumulation. ..."_

Here's the paper:

And here's some additional information about that pathway from an earlier paper:

"Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis."

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