Cleavage and reduced CD36 ectodomain density on heart and spleen macrophages in the Spontaneously Hypertensive Rat

Santamaria, Marco H.; Chen, Angela; Chow, Jason; Muñoz, Diana C.; Schmid‐Schönbein, Geert W.

doi:10.1016/j.mvr.2014.08.004

Cited by 9 publications

(10 citation statements)

References 47 publications

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“…Notably, chronic treatment with MMP inhibitors reduced receptor cleavage, blood pressure and insulin resistance in SHRs and increased capillary density, which supports the importance of increased MMP activity in the pathophysiology of hypertension and its comorbidities [19,20]. A similar mechanism of proteolytic receptor cleavage is observed in other comorbidities, such as deficiencies in immune function (e.g., leukocyte adhesion), leukocyte mechanotransduction, macrophage functions and cleavage of the glycocalyx in SHRs [26][27][28][29][30].…”

Section: Introductionsupporting

confidence: 55%

IGF-1 receptor cleavage in hypertension

Cırrık

Schmid‐Schönbein

2018

Hypertens Res

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Increased protease activity causes receptor dysfunction due to extracellular cleavage of different membrane receptors in hypertension. The vasodilatory effects of insulin-like growth factor-1 (IGF-1) are decreased in hypertension. Therefore, in the present study the association of an enhanced protease activity and IGF-1 receptor cleavage was investigated using the spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto (WKY) controls (n = 4). Matrix metalloproteinase (MMP) activities were determined using gelatin zymography on plasma and different tissue samples. WKY aorta rings were incubated in WKY or SHR plasma with or without MMP inhibitors, and immunohistochemistry was used to quantify the densities of the alpha and beta IGF-1 receptor (IGF-1R) subunits and to determine receptor cleavage. The pAkt and peNOS levels in the aorta were investigated using immunoblotting as a measure of IGF-IR function. Increased MMP-2 and MMP-9 activities were detected in plasma and peripheral tissues of SHRs. IGF-1R beta labeling was similar in both groups without plasma incubation, but the fraction of immunolabeled area for IGF-1R alpha was lower in the endothelial layer of the SHR aorta (p < 0.05). A 24-h incubation of WKY aorta with SHR plasma did not affect the IGF-1R beta labeling density, but reduced the IGF-1R alpha labeling density in the endothelium (p < 0.05). MMP inhibitors prevented this decrease (p < 0.01). Western blot analyses revealed that the pAkt and peNOS levels under IGF-1-stimulated and -unstimulated conditions were lower in SHRs (p < 0.05). A reduced IGF-1 cellular response in the aorta was associated with the decrease in the IGF-1R alpha subunit in the SHR hypertension model. Our results indicate that MMP-dependent receptor cleavage contributed to the reduced IGF-1 response in SHRs.

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Section: Introductionsupporting

confidence: 55%

IGF-1 receptor cleavage in hypertension

Cırrık

Schmid‐Schönbein

2018

Hypertens Res

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“…For example, an inactivated form of CD36, solCD36, has been identified in both murine and human plasma after MI, implicating a natural mechanism of CD36 inactivation after infarction (59). The proteases matrix metalloproteinase 9 and ADAM17 have both been implicated in the cleavage of the CD36 ectodomain from the surface of macrophages (24,59,60). The soluble remnants of these cleaved products can function as decoy receptors, inhibiting interaction between surface receptors and their dead cellular targets (61).…”

Section: Discussionmentioning

confidence: 99%

Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1‐dependent mechanisms of cardiac repair

Dehn¹,

Thorp²

2017

FASEB j.

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Phagocytosis after myocardial infarction (MI) is a prerequisite to cardiac repair. Recruited monocytes clear necrotic cardiomyocytes and differentiate into cardiac macrophages. Some studies have linked apoptotic cell receptors on cardiac macrophages to tissue repair; however, the contribution of precursor monocyte phagocytic receptors, which are the first to interact with the cardiac parenchyma, is unclear. The scavenger receptor cluster of differentiation (CD)36 protein was detected on cardiac Ly6cHI monocytes, and bone marrow-derived was essential for both early phagocytosis of dying cardiomyocytes and for smaller infarct sizes in female and male mice after permanent coronary ligation. deficiency led to reduced expression of phagocytosis receptor and nuclear receptor in cardiac macrophages, the latter previously shown to be required for phagocyte survival. was required for phagocytosis-induced expression, and Nr4a1 protein directly bound to gene regulatory elements. To test the overall contribution of the axis, MI was induced in double-knockout mice and led to increases in myocardial rupture. These data implicate monocyte CD36 in the mitigation of early infarct size and transition todependent macrophage function. Increased myocardial rupture in the absence of both and underscore the physiologic significance of phagocytosis during tissue injury.-Dehn, S., Thorp, E. B. Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair.

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“…Besides elevated white cell count, indices of inflammation and high levels of oxygen free radicals [36], this rat strain exhibits elevated levels of protease activity in plasma, including MMP-2, MMP-9 (gelatinase A and B), MMP-8, and MMP-7 (matrilysin) [35,37]. While the elevations of plasma MMP activity are modest (about 10 and 25% above the low pressure control strain) they are permanently elevated and accompanied by reduced levels of tissue inhibitor of metalloproteases 1 (TIMP-1,2) [38]. The enhanced MMP activity is accompanied by elevated MMP protein levels, as detected with immunohistochemistry [35].…”

Section: Proteolytic Receptor Cleavage and Co-morbidities In The Smentioning

confidence: 99%

“…If the SHR is chronically treated with MMP inhibitors (e.g. doxycycline at a sub-antibiotic dose level, CGS27023A), its plasma and endothelial MMP activity is reduced to levels of the normotensive WKY rats, its elevated blood pressure is normalized and its β 2 adrenergic receptor population is restored [35,38]. …”

Section: Proteolytic Receptor Cleavage and Co-morbidities In The Smentioning

confidence: 99%

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

Mazor

Schmid‐Schönbein

2016

BIR

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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.

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Cleavage and reduced CD36 ectodomain density on heart and spleen macrophages in the Spontaneously Hypertensive Rat

Cited by 9 publications

References 47 publications

IGF-1 receptor cleavage in hypertension

IGF-1 receptor cleavage in hypertension

Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1‐dependent mechanisms of cardiac repair

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

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