title: Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion.
abstract: 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.
authors.affiliation: Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Rafi
authors.initials: R
authors.lastname: Mazor
authors.affiliation: Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
mesh_terms: D000818:Animals; D018056:Hemorheology / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular; D008659:Metabolic Diseases / Q000378:metabolism / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D054411:Receptors, Leptin; D011972:Receptor, Insulin; D040301:Vascular Endothelial Growth Factor Receptor-2; D010447:Peptide Hydrolases
keywords: Matrix metalloproteinase; autodigestion; cell rheology; hypertension; insulin resistance; mechanotransduction; pancreatic digestive enzyme; rarefaction; serine protease; spontaneously hypertensive rat