Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat.

F A DeLano, Geert W Schmid-Schönbein


Arterial hypertension is associated with organ dysfunctions, but the mechanisms are uncertain. We hypothesized that enhanced proteolytic activity in the microcirculation of spontaneously hypertensive rats (SHRs) may be a pathophysiological mechanism causing cell membrane receptor cleavage and examine this for 2 different receptors. Immunohistochemistry of matrix-degrading metalloproteinases (matrix metalloproteinase [MMP]-9) protein shows enhanced levels in SHR microvessels, mast cells, and leukocytes compared with normotensive Wistar-Kyoto rats. In vivo microzymography shows cleavage by MMP-1 and -9 in SHRs that colocalizes with MMP-9 and is blocked by metal chelation. SHR plasma also has enhanced protease activity. We demonstrate with an antibody against the extracellular domain that the insulin receptor-alpha density is reduced in SHRs, in line with elevated blood glucose levels and glycohemoglobin. There is also cleavage of the binding domain of the leukocyte integrin receptor CD18 in line with previously reported reduced leukocyte adhesion. Blockade of MMPs with a broad-acting inhibitor (doxycycline, 5.4 mg/kg per day) reduces protease activity in plasma and microvessels; blocks the proteolytic cleavage of the insulin rece...Continue Reading


Dec 1, 1976·Journal of Pharmaceutical Sciences·E C Newman, C W Frank
Mar 1, 1991·Hypertension·G W Schmid-SchönbeinB W Zweifach
Oct 1, 1995·The Journal of Clinical Investigation·M SuematsuY Ishimura
Apr 1, 1996·Hypertension·L A SechiM Schambelan
May 1, 1996·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·G A RosenbergG Feuerstein
Feb 26, 1996·FEBS Letters·E R FrearsP G Winyard
Jul 1, 1995·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·K ShenG W Schmid-Schönbein
Feb 11, 1999·Advances in Dental Research·M E RyanL M Golub
Mar 9, 2000·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·S TakaseG W Schmid-Schönbein
Jul 19, 2000·American Journal of Physiology. Heart and Circulatory Physiology·D M LendaM A Boegehold
Jul 20, 2001·International Journal of Cardiology·V S MujumdarS C Tyagi
Mar 23, 2002·Circulation Research·Francis G Spinale
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Aug 19, 2003·Journal of Hypertension·Teresa M CampSuresh C Tyagi
Jan 14, 2004·Journal of Atherosclerosis and Thrombosis·Masafumi Kuzuya, Akihisa Iguchi
Jan 15, 2005·American Journal of Physiology. Heart and Circulatory Physiology·F A DeLanoG W Schmid-Schönbein
Feb 25, 2005·Investigative Ophthalmology & Visual Science·Hyun-Seung KimDe-Quan Li
Mar 29, 2005·Molecular and Cellular Biochemistry·Michael O GriffinFrancisco J Villarreal
Jul 23, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·Nobuhiko KobayashiGeert W Schmid-Schönbein
Sep 23, 2006·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Frank A DeLanoGeert W Schmid-Schönbein

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Sep 24, 2010·American Journal of Physiology. Cell Physiology·Angela Y ChenGeert W Schmid-Schönbein
Apr 20, 2010·American Journal of Physiology. Heart and Circulatory Physiology·Theodore J Kalogeris, Ronald J Korthuis
Apr 13, 2010·American Journal of Physiology. Heart and Circulatory Physiology·Stephen F RodriguesGeert W Schmid-Schönbein
Dec 15, 2010·American Journal of Physiology. Heart and Circulatory Physiology·Herbert H LipowskyAnne Lescanic
Apr 6, 2011·Journal of Vascular Research·Sheng TongGeert W Schmid-Schönbein
May 9, 2012·Journal of Leukocyte Biology·Angela Y ChenGeert W Schmid-Schönbein
Aug 31, 2013·Annals of Biomedical Engineering·Geert W Schmid-Schönbein, Marisol Chang
Sep 26, 2013·Microvascular Research·Naphatsanan Duansak, Geert W Schmid-Schönbein
Dec 1, 2011·Cellular and Molecular Bioengineering·Cécile PotGeert W Schmid-Schönbein
May 1, 2012·Cellular and Molecular Bioengineering·Angelina E AltshulerGeert W Schmid-Schönbein
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Nov 6, 2009·Clinical and Experimental Hypertension : CHE·Ryan S FrieseDaniel T O'Connor
Dec 29, 2015·The Journal of Physical Chemistry. B·Birgit J WaldnerKlaus R Liedl
Nov 15, 2011·Drug Discovery Today. Disease Models·F A DelanoG W Schmid-Schönbein
Nov 30, 2011·Drug Discovery Today. Disease Models·Luis A Martinez-Lemus, Edgar Luis Galiñanes
Nov 8, 2011·Drug Discovery Today. Disease Models·Herbert H Lipowsky
Nov 30, 2011·Drug Discovery Today. Disease Models·George E Davis
Dec 1, 2009·European Journal of Pharmacology·Rong LiFeng Gao
Mar 21, 2016·Biosensors & Bioelectronics·Ee Xien NgChia-Hung Chen
Mar 23, 2011·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Edward D TranGeert W Schmid-Schönbein
Jul 1, 2014·Basic & Clinical Pharmacology & Toxicology·Aline AzevedoRaquel F Gerlach
Jun 29, 2010·Electrophoresis·Roy B LefkowitzMichael J Heller
Jan 11, 2014·International Journal of Cardiology·Kazuhide OginoWolfram Doehner
Aug 31, 2014·Microvascular Research·Marco H SantamariaGeert W Schmid-Schönbein
Feb 14, 2009·American Journal of Hypertension·Kwok Leung OngBernard M Y Cheung
Oct 21, 2016·Journal of Periodontology·Aliye AkcalıNurcan Buduneli
Apr 20, 2017·The Journal of Trauma and Acute Care Surgery·Marco Henry SantamariaErik B Kistler
Mar 21, 2018·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Selma Cirrik, Geert W Schmid-Schönbein

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