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.

Association of MMP‐8 with obesity, smoking and insulin resistance

“…Hiriart et al [11] have found that hyperinsulinaemia is associated with increased soluble insulin receptors release from hepatocytes, which could lead to higher amounts of insulin bound to this receptor instead of free insulin, which is the biologically active form of the hormone. Schmid-Sch€ onbein and coworker [13,14] have suggested that metabolic syndrome with complications like diabetes, elevated blood pressure as well as abnormal vascular rheology is due to uncontrolled extracellular proteolytic activity that causes receptor cleavage. Schmid-Sch€ onbein and coworker [13,14] have suggested that metabolic syndrome with complications like diabetes, elevated blood pressure as well as abnormal vascular rheology is due to uncontrolled extracellular proteolytic activity that causes receptor cleavage.…”

“…El Mesallamy et al have found that both obesity and type 2 diabetes are associated with increased serine protease plasma granzyme B, which correlate with inflammation, insulin receptor cleavage and insulin resistance [12]. Schmid-Sch€ onbein and coworker [13,14] have suggested that metabolic syndrome with complications like diabetes, elevated blood pressure as well as abnormal vascular rheology is due to uncontrolled extracellular proteolytic activity that causes receptor cleavage. Delano et al [15] have proposed that a mechanism of action of insulin resistance in obesity is insulin receptor cleavage by increased proteinase activity, especially MMP-1 and MMP-9.…”

Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

“…Elevation of plasma protease activity was shown to be associated with diet-induced obesity and insulin resistance or chronic inflammation [3][4][5][6][7][8][9] . Badeanlou et al reported that diet-induced insulin resistance required protease-activated receptor 2 signaling activation 3 .…”

“…Furthermore, α1-antitrypsin has been shown to prevent type 1 diabetes development, prolong islet allograft survival, and inhibit pancreatic β-cell apoptosis in vivo 8 . Chronic inflammation-induced proteolytic matrix metalloproteinases cleave the extracellular domains of insulin receptors, induce soluble insulin receptor-α in human plasma, and promote insulin resistance 9 . Interestingly, the recent evidence showed that the soluble insulin-receptor ectodomain is elevated in the plasma of patients with diabetes 10 , and the serine protease granzyme B is an inflammatory marker related to insulin receptor cleavage in human obesity and type 2 diabetes mellitus 11 .…”

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

“…For example, it is not clear what role protease-dependent receptor cleavage (Schmid-Schonbein, 2016; Mazor & Schmid-Schonbein, 2015) might play in postischemic EDD dysfunction. Moreover, interesting recent work has demonstrated that pentraxin 3, a soluble pattern recognition receptor that plays an important role in innate immune responses, induces EDD dysfunction via a P-selectin/MMP-dependent pathway that may feed into our hypothesized mechanism (Carrizzo, Lenzi, Procaccini, Damato, Biagioni, Ambrosio et al, 2015).…”