Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis.

Abstract:

:Prolylcarboxypeptidase (PRCP) activates prekallikrein to plasma kallikrein, leading to bradykinin liberation, and degrades angiotensin II. We now identify PRCP as a regulator of blood vessel homeostasis. β-Galactosidase staining in PRCP(gt/gt) mice reveals expression in kidney and vasculature. Invasive telemetric monitorings show that PRCP(gt/gt) mice have significantly elevated blood pressure. PRCP(gt/gt) mice demonstrate shorter carotid artery occlusion times in 2 models, and their plasmas have increased thrombin generation times. Pharmacologic inhibition of PRCP with Z-Pro-Prolinal or plasma kallikrein with soybean trypsin inhibitor, Pro-Phe-Arg-chloromethylketone or PKSI 527 also shortens carotid artery occlusion times. Aortic and renal tissues have uncoupled eNOS and increased reactive oxygen species (ROS) in PRCP(gt/gt) mice as detected by dihydroethidium or Amplex Red fluorescence or lucigenin luminescence. The importance of ROS is evidenced by the fact that treatment of PRCP(gt/gt) mice with antioxidants (mitoTEMPO, apocynin, Tempol) abrogates the hypertensive, prothrombotic phenotype. Mechanistically, our studies reveal that PRCP(gt/gt) aortas express reduced levels of Kruppel-like factors 2 and 4, thrombomodulin, and eNOS mRNA, suggesting endothelial cell dysfunction. Further, PRCP siRNA treatment of endothelial cells shows increased ROS and uncoupled eNOS and decreased protein C activation because of thrombomodulin inactivation. Collectively, our studies identify PRCP as a novel regulator of vascular ROS and homeostasis.

journal_name

Blood

journal_title

Blood

authors

Adams GN,LaRusch GA,Stavrou E,Zhou Y,Nieman MT,Jacobs GH,Cui Y,Lu Y,Jain MK,Mahdi F,Shariat-Madar Z,Okada Y,D'Alecy LG,Schmaier AH

doi

10.1182/blood-2010-11-318527

subject

Has Abstract

pub_date

2011-04-07 00:00:00

pages

3929-37

issue

14

eissn

0006-4971

issn

1528-0020

pii

blood-2010-11-318527

journal_volume

117

pub_type

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