In addition to enhanced arterial blood pressure, hypertensives have inflammatory mechanisms that cause microvascular and parenchymal cell dysfunction, apoptosis, and lesion formation. It is our long-term objective to identify these inflammatory mechanisms in the microcirculation where early detection is possible before development of overt clinical signs. We hypothesize that besides enhanced oxygen radical formation, the microcirculation of spontaneously hypertensive rats (SHRs) exhibits a greatly enhanced protease activity with over-expression of matrix metalloproteinases. The presence of proteolytic enzymes in the SHR causes cleavage of the extracellular domain of membrane receptors and loss of cell function, for example cleavage of the extracellular domain of the insulin receptor a or membrane adhesion molecule CD18 with loss of the ability to bind insulin and facilitate glucose transport or leukocyte adhesion, i.e. insulin resistance and immune suppression, respectively. We provide preliminary evidence that chronic MMP blockade in the SHR reduces receptor cleavage and annihilates insulin resistance, CD18 cleavage, and normalizes the blood pressure, oxygen free radical formation, and apoptosis.
Our Specific Aims are (1) to measure the activity and expression of MMPs in the microcirculation of the SHR and its normotensive controls (Wistar Kyoto rat and Wistar Rat);to measure the level of microvascular cell dysfunction and organ injury after blockade of the proteases;and identify mechanisms for activation of MMP preforms;(2) to determine the level of receptor cleavage and its role in microvascular cell dysfunction in the SHR and its controls;to measure membrane density before and after chronic MMP inhibition;to measure the ability of SHR plasma to acutely cleave receptors in-vitro on naive cells from the normotensive Wistar strain and the associated cell dysfunction;(3) determine signaling pathways in the SHR that lead to MMP expression in microvascular endothelium, leukocytes, and interstitial cells that involve superoxide formation and nuclear factor NFkB activation. We will apply new experimental techniques to measure protease activity in a living microcirculation, measure protein and message levels of proteases in a complete microvascular network with high and low pressure domains as a tool to identify pressure mediated mechanisms. We will determine to what degree blockade of protease activity prevents receptor cleavage and cell dysfunctions in the SHR. We will identify specific enzymatic activity in the microcirculation as therapeutic target in the future to attenuate inflammatory processes in hypertensives. The research program serves the first time to unify a diverse set of pathogenic mechanisms in the SHR under one mechanistic hypothesis and at the same time open the opportunity for new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL010881-43
Application #
7787433
Study Section
Special Emphasis Panel (ZRG1-CVS-N (02))
Program Officer
Wood, Katherine
Project Start
1978-09-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
43
Fiscal Year
2010
Total Cost
$309,000
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Akenhead, Michael L; Fukuda, Shunichi; Schmid-Schönbein, Geert W et al. (2017) Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion. J Leukoc Biol 102:117-126
Mazor, Rafi; Schmid-Schönbein, Geert W (2015) Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion. Biorheology 52:337-52
Santamaria, Marco H; Chen, Angela Y; Chow, Jason et al. (2014) Cleavage and reduced CD36 ectodomain density on heart and spleen macrophages in the spontaneously hypertensive rat. Microvasc Res 95:131-42
Duansak, Naphatsanan; Schmid-Schönbein, Geert W (2013) The oxygen free radicals control MMP-9 and transcription factors expression in the spontaneously hypertensive rat. Microvasc Res 90:154-61
Mazor, Rafi; Alsaigh, Tom; Shaked, Helena et al. (2013) Matrix metalloproteinase-1-mediated up-regulation of vascular endothelial growth factor-2 in endothelial cells. J Biol Chem 288:598-607
Friese, Ryan S; Altshuler, Angelina E; Zhang, Kuixing et al. (2013) MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension. Hum Mol Genet 22:3624-40
Schmid-Schönbein, Geert W (2012) An emerging role of degrading proteinases in hypertension and the metabolic syndrome: autodigestion and receptor cleavage. Curr Hypertens Rep 14:88-96
Chen, Angela Y; Ha, Jessica N; Delano, Frank A et al. (2012) Receptor cleavage and P-selectin-dependent reduction of leukocyte adhesion in the spontaneously hypertensive rat. J Leukoc Biol 92:183-94
Altshuler, Angelina E; Morgan, Mary J; Chien, Shu et al. (2012) Proteolytic Activity Attenuates the Response of Endothelial Cells to Fluid Shear Stress. Cell Mol Bioeng 5:82-91
Schmid-Schonbein, Geert W (2012) Nitric oxide (NO) side of lymphatic flow and immune surveillance. Proc Natl Acad Sci U S A 109:3-4

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