PMID- 28941979
OWN - NLM
STAT- MEDLINE
DCOM- 20171129
LR  - 20231213
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 187
IP  - 12
DP  - 2017 Dec
TI  - Proteolytic Degradation and Inflammation Play Critical Roles in Polypoidal 
      Choroidal Vasculopathy.
PG  - 2841-2857
LID - S0002-9440(17)30443-1 [pii]
LID - 10.1016/j.ajpath.2017.08.025 [doi]
AB  - Polypoidal choroidal vasculopathy (PCV) is a common subtype of wet age-related 
      macular degeneration in Asian populations, whereas choroidal neovascularization 
      is the typical subtype in Western populations. The cause of PCV is unknown. By 
      comparing the phenotype of a PCV mouse model expressing protease high temperature 
      requirement factor A1 (HTRA1) in retinal pigment epithelium with transgenic mice 
      expressing the inactive HTRA1(S328A), we showed that HTRA1-mediated degradation 
      of elastin in choroidal vessels is critical for the development of PCV, which 
      exhibited destructive extracellular matrix remodeling and vascular smooth muscle 
      cell loss. Compared with weak PCV, severe PCV exhibited prominent immune complex 
      deposition, complement activation, and infiltration of inflammatory cells, 
      suggesting inflammation plays a key role in PCV progression. More important, we 
      validated these findings in human PCV specimens. Intravitreal delivery of an 
      HTRA1 inhibitor (DPMFKLboroV) was effective (36% lesion reduction; P = 0.009) in 
      preventing PCV initiation but ineffective in treating existing lesions. 
      Anti-inflammatory glucocorticoid was effective in preventing PCV progression but 
      ineffective in preventing PCV initiation. These results suggest that PCV 
      pathogenesis occurs through two stages. The initiation stage is mediated by 
      proteolytic degradation of extracellular matrix proteins attributable to 
      increased HTRA1 activity, whereas the progression stage is driven by inflammatory 
      cascades. This study provides a basis for understanding the differences between 
      PCV and choroidal neovascularization, and helps guide the design of effective 
      therapies for PCV.
CI  - Copyright (c) 2017 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Kumar, Sandeep
AU  - Kumar S
AD  - Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
FAU - Nakashizuka, Hiroyuki
AU  - Nakashizuka H
AD  - Department of Visual Sciences, Nihon University School of Medicine, Tokyo, Japan.
FAU - Jones, Alex
AU  - Jones A
AD  - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake 
      City, Utah.
FAU - Lambert, Alyssia
AU  - Lambert A
AD  - Department of Chemistry, University of Utah, Salt Lake City, Utah.
FAU - Zhao, Xuchen
AU  - Zhao X
AD  - Department of Chemistry, University of Utah, Salt Lake City, Utah.
FAU - Shen, Megan
AU  - Shen M
AD  - Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
FAU - Parker, Mackenzie
AU  - Parker M
AD  - Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
FAU - Wang, Shixian
AU  - Wang S
AD  - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake 
      City, Utah.
FAU - Berriochoa, Zachary
AU  - Berriochoa Z
AD  - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake 
      City, Utah.
FAU - Fnu, Amrita
AU  - Fnu A
AD  - Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
FAU - VanBeuge, Stephanie
AU  - VanBeuge S
AD  - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake 
      City, Utah.
FAU - Chevez-Barrios, Patricia
AU  - Chevez-Barrios P
AD  - Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 
      Houston, Texas.
FAU - Tso, Mark
AU  - Tso M
AD  - Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland.
FAU - Rainier, Jon
AU  - Rainier J
AD  - Department of Chemistry, University of Utah, Salt Lake City, Utah.
FAU - Fu, Yingbin
AU  - Fu Y
AD  - Department of Ophthalmology, Baylor College of Medicine, Houston, Texas; 
      Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake 
      City, Utah. Electronic address: yingbin.fu@bcm.edu.
LA  - eng
GR  - P30 EY002520/EY/NEI NIH HHS/United States
GR  - P30 EY014800/EY/NEI NIH HHS/United States
GR  - R01 EY022901/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20170921
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - EC 3.4.21.- (High-Temperature Requirement A Serine Peptidase 1)
RN  - EC 3.4.21.- (HTRA1 protein, human)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Choroidal Neovascularization/metabolism/pathology
MH  - Female
MH  - High-Temperature Requirement A Serine Peptidase 1/*metabolism
MH  - Humans
MH  - Inflammation/pathology
MH  - Macular Degeneration/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Proteolysis
MH  - Wet Macular Degeneration/metabolism/*pathology
PMC - PMC5718105
EDAT- 2017/09/25 06:00
MHDA- 2017/12/01 06:00
PMCR- 2018/12/01
CRDT- 2017/09/25 06:00
PHST- 2017/04/19 00:00 [received]
PHST- 2017/07/31 00:00 [revised]
PHST- 2017/08/17 00:00 [accepted]
PHST- 2017/09/25 06:00 [pubmed]
PHST- 2017/12/01 06:00 [medline]
PHST- 2017/09/25 06:00 [entrez]
PHST- 2018/12/01 00:00 [pmc-release]
AID - S0002-9440(17)30443-1 [pii]
AID - 10.1016/j.ajpath.2017.08.025 [doi]
PST - ppublish
SO  - Am J Pathol. 2017 Dec;187(12):2841-2857. doi: 10.1016/j.ajpath.2017.08.025. Epub 
      2017 Sep 21.