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Ericka Oglesby, Julie Schaub, Elizabeth Cone-Kimball, Mary Ellen Pease, Ian Pitha, Harry A Quigley; Losartan inhibits myofibroblast transdifferentiation of human scleral fibroblasts. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4604.
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© ARVO (1962-2015); The Authors (2016-present)
Systemic losartan treatment prevents retinal ganglion cell (RGC) death in murine, bead-induced glaucoma by altering the scleral response to IOP-glaucoma. The sclera is a fibrous connective tissue consisting of fibroblasts embedded in an extracellular matrix (ECM) predominately consisting of type I collagen. Upon glaucoma induction, scleral fibroblasts express markers of myofibroblast transdifferentiation. We hypothesize that losartan prevents scleral remodeling during glaucoma by preventing myofibroblast transdifferentiation of scleral fibroblasts.
Primary, peripapillary scleral (PPS) fibroblasts were isolated from the sclera of a human donor with no known history of glaucoma. Between passages 3 and 12, cells were treated with the transdifferentiation-inducing molecules, transforming growth factor-beta (TGFβ) or endothelin-1 (ET-1). To assess myofibroblast transdifferentiation, alpha smooth muscle actin (αSMA) expression was evaluated by immunoblot analysis. To test the ability of ARBs to inhibit myofibroblast differentiation, cells were pretreated with the angiotensin receptor blockers (ARB), losartan, irbesartan, or candesartan (1 mM, 100 µM, 10 µM, 1 µM, and 0.1 µM), prior to exposure to TGFβ or ET-1.
αSMA expression was induced within 24 hours following treatment with 1 ng/ml TGFβ and 5 nm ET-1. Treatment with losartan, irbesartan, or candesartan (up to 1 mM) did not alter cellular αSMA expression or proliferation. Treatment with micromolar dosages of ARBs prior to TGFβ and ET-1 exposure reduced myofibroblast transdifferentiation as demonstrated by reduced αSMA induction.
ARBs prevent myofibroblast transdifferentiation in cultured human, PPS fibroblasts. These results suggest that scleral fibroblast behavior can be pharmacologically modified to prevent glaucomatous RGC death.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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