This Article Free upon publication Full Text Full Text (PDF) All Versions of this Article: 38/9/2598    most recent STROKEAHA.106.480103v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xu, F. Articles by Van Nostrand, W. E. Search for Related Content PubMed PubMed Citation Articles by Xu, F. Articles by Van Nostrand, W. E. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Related Collections Animal models of human disease Arterial thrombosis Coagulation Acute Cerebral Hemorrhage

(Stroke. 2007;38:2598.)
© 2007 American Heart Association, Inc.

Research Letters

Increased Severity of Hemorrhage in Transgenic Mice Expressing Cerebral Protease Nexin-2/Amyloid ß-Protein Precursor

Feng Xu, MD; Mary Lou Previti, BS William E. Van Nostrand, PhD

From the Department of Medicine, Stony Brook University, Stony Brook, NY.

Correspondence to Dr William E. Van Nostrand, Department of Medicine, HSC T-15/083, Stony Brook University, Stony Brook, NY 11794-8153. E-mail William.VanNostrand{at}stonybrook.edu

Abstract

Background and Purpose— Secreted isoforms of amyloid ß-protein precursor (AßPP) that contain the Kunitz proteinase inhibitor domain, also known as protease nexin-2 (PN2), are enriched in brain. Although little is known of its physiological function, the potent inhibition of certain prothrombotic proteinases by PN2/AßPP suggests that it may function to regulate cerebral thrombosis during vascular injury events.

Methods— To examine the antithrombotic function of cerebral PN2/AßPP in vivo, we performed measurements of carotid artery thrombosis and experimental intracerebral hemorrhage in transgenic mice with specific and modest overexpression of PN2/AßPP in brain. Comparisons were made with wild-type mice and Tg-rPF4/APP mice, a model that possesses specific and modest overexpression of PN2/AßPP in platelets and exhibits reduced thrombosis in vivo.

Results— Modest overexpression of PN2/AßPP in transgenic mouse brain had no effect on intraluminal carotid arterial thrombosis but resulted in larger hematoma volumes and hemoglobin levels (23.1±2.7 mm³ [n=6; P<0.01] and 1411±202 µg/hemisphere [n=12; P<0.01], respectively), compared with wild-type mice (15.9±2.2 mm³ [n=6] and 935±418 µg/hemisphere [n=12], respectively).

Conclusions— These findings indicate that cerebral PN2/AßPP plays a significant role in regulating thrombosis in brain and that modest age-related increases in the cerebral levels of this protein could markedly enhance the extent of cerebral hemorrhage.

Key Words: ß-amyloid precursor protein • intracerebral hemorrhage • proteinase inhibitor • thrombosis • transgenic

This article has been cited by other articles:

				F. Xu, M. L. Previti, M. T. Nieman, J. Davis, A. H. Schmaier, and W. E. Van Nostrand A{beta}PP/APLP2 Family of Kunitz Serine Proteinase Inhibitors Regulate Cerebral Thrombosis J. Neurosci., April 29, 2009; 29(17): 5666 - 5670. [Abstract] [Full Text] [PDF]