Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Chen, Angela; DeLano, Frank A.; Valdez, Shakti; Ha, Jessica N.; Shin, Hainsworth Y.; Schmid‐Schönbein, Geert W.

doi:10.1152/ajpcell.00157.2010

Cited by 32 publications

(38 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When this receptor is cleaved, neutrophils become non-responsive not only to formyl peptides (e.g. F-Met-Leu-Phe) but also to fluid shear stress [24]. Consequently one finds enhanced levels of pseudopod formation by leukocytes in the circulation and they are subject not only to entrapment in capillaries but also they cause increased capillary hemodynamic resistance by disturbing the motion of red cells in single file capillaries [25,26].…”

Section: Compromise Of Blood Rheology In the Presence Of Degradingmentioning

confidence: 99%

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

Mazor

Schmid‐Schönbein

2016

BIR

Self Cite

View full text Add to dashboard Cite

Abnormal blood rheological properties seldom occur in isolation and instead are accompanied by other complications, often designated as co-morbidities. In the metabolic syndrome with complications like hypertension, diabetes and lack of normal microvascular blood flow, the underlying molecular mechanisms that simultaneously lead to elevated blood pressure and diabetes as well as abnormal microvascular rheology and other cell dysfunctions have remained largely unknown. In this review, we propose a new hypothesis for the origin of abnormal cell functions as well as multiple co-morbidities. Utilizing experimental models for the metabolic disease with diverse co-morbidities we summarize evidence for the presence of an uncontrolled extracellular proteolytic activity that causes ectodomain receptor cleavage and loss of their associated cell function. We summarize evidence for unchecked degrading proteinase activity, e.g. due to matrix metalloproteases, in patients with hypertension, Type II diabetes and obesity, in addition to evidence for receptor cleavage in the form of receptor fragments and decreased extracellular membrane expression levels. The evidence suggest that a shift in blood rheological properties and other co-morbidities may in fact be derived from a common mechanism that is due to uncontrolled proteolytic activity, i.e. an early form of autodigestion. Identification of the particular proteases involved and the mechanisms of their activation may open the door to treatment that simultaneously targets multiple co-morbidities in the metabolic syndrome.

show abstract

Section: Compromise Of Blood Rheology In the Presence Of Degradingmentioning

confidence: 99%

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

Mazor

Schmid‐Schönbein

2016

BIR

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cleavage of the vasodilating β 2 -adrenergic GPCR by MMPs impairs the relaxation of vascular smooth muscle [61]. MMPs can also modulate blood pressure independently of vascular tone by degrading the formyl peptide GPCR, causing reduced pseudopod retraction of leukocytes in response to shear stress, which results in increased hemodynamic resistance in capillaries that contributes to elevated blood pressure [62]. MMPs may additionally contribute to complications of hypertension by cleaving the vascular endothelial growth factor receptor-2 to cause microvascular rarefaction and endothelial apoptosis, and the insulin receptor to cause insulin resistance [63,64].…”

Section: Substrates Of Mmps and Adams In Hypertensive Cardiac Diseasementioning

confidence: 99%

Insights into the Activity, Differential Expression, Mutual Regulation, and Functions of Matrix Metalloproteinases and A Disintegrin and Metalloproteinases in Hypertension and Cardiac Disease

Berry

Bosonea²,

Wang³

et al. 2012

J Vasc Res

View full text Add to dashboard Cite

Hypertensive cardiac disease is a major cause of death worldwide. Causative factors of hypertension include environmental stressors, genetic predisposition, and common morbidities of lipid metabolism such as obesity and diabetes. These factors pathologically elevate the systemic production of vasoconstrictive G-protein-coupled receptor agonists. Pathological concentrations of these agonists upregulate the gene expression and proteolytic activity of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). Among the metalloproteinases that act in concert with other mediators to elevate the systemic blood pressure and to modulate the development of cardiovascular hypertrophy and fibrosis processes are MMP-2, MMP-7, ADAM-12, and ADAM-17. This review offers insights into the activity, differential expression, mutual regulation, and functions of these metalloproteinases. We further review evidence linking them to transcription factors, carrier proteins, and receptors for lipids. The emerging links between metalloproteinases and lipids are intriguing and suggest new therapeutic targets in hypertensive cardiac disease.

show abstract

“…It is also possible that altered regulation of superoxide and nitric oxide levels related to hypercholesterolemia (22) impaired PMNL responses to shear since both of these molecules are involved in the leukocyte shear-response and exhibit membrane solubility (15,23). In addition, the reduced PMNL shear-responses may be attributable to an enhanced cleavage of membranebound receptors such as shear-sensitive FPRs (9). However, the fact that the effects of these factors (e.g., proinflammatory agonists, superoxide/nitric oxide, receptor cleavage) together with additional contributors, such as other HFD components and age, account for the remaining Ϸ50% of the variances associated with hypercholesterolemia-related attenuation of PMNL shear-responses further supports the important and dominant role of cholesterol.…”

Section: C457 Membrane Fluidity In the Leukocyte Shear-responsementioning

confidence: 99%

Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity

Zhang

Hurng

Rateri

et al. 2011

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

Specifically, fluid flow-derived shear stresses deactivate leukocytes via actions on the conformational activities of proteins on the cell surface. Because membrane properties affect activities of membranebound proteins, we hypothesized that changes in the physical properties of cell membranes influence PMNL sensitivity to fluid shear stress. For this purpose, we modified PMNL membranes and showed that the cellular mechanosensitivity to shear was impaired whether we increased, reduced, or disrupted the organization of cholesterol within the lipid bilayer. Notably, PMNLs with enriched membrane cholesterol exhibited attenuated pseudopod retraction responses to shear that were recovered by select concentrations of benzyl alcohol (a membrane fluidizer). In fact, PMNL responses to shear positively correlated (R 2 ϭ 0.96; P Ͻ 0.0001) with cholesterol-related membrane fluidity. Moreover, in low-density lipoprotein receptor-deficient (LDLr Ϫ/Ϫ ) mice fed a high-fat diet (a hypercholesterolemia model), PMNL shear-responses correlated (R 2 ϭ 0.5; P Ͻ 0.01) with blood concentrations of unesterified (i.e., free) cholesterol. In this regard, the shear-responses of PMNLs gradually diminished and eventually reversed as free cholesterol levels in blood increased during 8 wk of the high-fat diet. Collectively, our results provided evidence that cholesterol is an important component of the PMNL mechanotransducing capacity and elevated membrane cholesterol impairs PMNL shearresponses at least partially through its impact on membrane fluidity. This cholesterol-linked perturbation may contribute to dysregulated PMNL activity (e.g., chronic inflammation) related to hypercholesterolemia and causal for cardiovascular pathologies (e.g., atherosclerosis).flow; cell deactivation; pseudopod retraction; mechanotransduction; hypercholesterolemia WHETHER ADHERED TO A SURFACE or freely suspended in plasma, polymorphonuclear leukocytes (PMNLs; particularly neutrophils) sense and respond to fluid shear stress (force per unit area acting tangential to the cell surface; dyn/cm 2 ) imposed by blood flow. Specifically, fluid shear stress maintains PMNLs in a deactivated state by reducing or preventing formation of pseudopod(s), a morphological hallmark of an activated PMNL, while at the same time, promoting cleavage of cell surface-associated ␤ 2 (CD18) integrins involved in cell adhesion and migration (30,48). The cell-inactivating action of shear stress is depressed upon treatment of cells with threshold concentrations of biochemical agonists, such as formyl peptide (N-formyl-Met-LeuPhe or FMLP; Ͼ 0.01 M) and platelet-activating factor (Ͼ0.1 M) (15), pointing to circulatory fluid flow as a negative mechano-regulator of PMNL activity in the absence of inflammatory agents, i.e., cell stimulation overrides this negative fluid shear stress control. Moreover, impaired leukocyte responses to shear stress, due to agonist stimulation or a pathologically inflamed state, have been linked to increased PMNL entrapment in the microcirculation of normotensive r...

show abstract

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Cited by 32 publications

References 43 publications

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

Insights into the Activity, Differential Expression, Mutual Regulation, and Functions of Matrix Metalloproteinases and A Disintegrin and Metalloproteinases in Hypertension and Cardiac Disease

Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity

Contact Info

Product

Resources

About