The autodigestion hypothesis and receptor cleavage in diabetes and hypertension

DeLano, Frank A.; Chen, A.Y.; Wu, K.-I. S.; Tran, Edward D.; Rodrigues, S.; Schmid‐Schönbein, Geert W.

doi:10.1016/j.ddmod.2011.05.002

Cited by 11 publications

(11 citation statements)

References 94 publications

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“…Compared to its normotensive control, the Wistar Kyoto Rat (WKY), MMP levels, specifically MMP-2 and MMP-9, in the SHR are elevated (Chen et al, 2012; DeLano & Schmid-Schönbein, 2008; Tran et al, 2010), leading to ectodomain receptor cleavage and cellular dysfunctions (Chen et al, 2010; Delano et al, 2011; DeLano & Schmid-Schönbein, 2008; Rodrigues et al, 2010; Tran et al, 2010) generating its co-morbidities, such as insulin resistance. Levels of the endogenous tissue inhibitors of metalloproteinases (TIMPs), such as TIMP-1 and TIMP-2 with the ability to inhibit MMP-9 and MMP-2, respectively (Bernardo & Fridman, 2003; Brumann et al, 2012) are undetermined and will be presented in this report.…”

Section: Introductionmentioning

confidence: 99%

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

Santamaria

Chen

Chow

et al. 2014

Microvascular Research

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Metabolic disease is accompanied by a range of cellular defects (“comorbidities”) whose origin is uncertain. To investigate this pathophysiological phenomenon we used the Spontaneously Hypertensive Rat (SHR), which besides an elevated arterial blood pressure also has many other comorbidities, including a defective glucose and lipid metabolism. We have shown that this model of metabolic disease has elevated plasma matrix metalloproteinase (MMP) activity, which cleaves the extracellular domain of membrane receptors. We hypothesize here that the increased MMP activity also leads to abnormal cleavage of the scavenger receptor and fatty acid transporter CD36. To test this idea, chronic pharmaceutical MMP inhibition (CGS27023A) of the SHR and its normotensive control, the Wistar Kyoto Rat (WKY), was used to determine if inhibition of MMP activity serves to maintain CD36 receptor density and function. Surface density of CD36 on macrophages from the heart, spleen, and liver was determined in WKY, SHR, CGS-treated WKY (CGS WKY), and CGS-treated SHR (CGS SHR) by immunohistochemistry with an antibody against the CD36 ectodomain. The extracellular CD36 density was lower in SHR heart and spleen macrophages compared to that in the WKY. MMP inhibition by CGS served to restore the reduced CD36 density on SHR cardiac and splanchnic macrophages to levels of the WKY. To examine CD36 function, culture assays with murine macrophages (RAW 264.7) after incubation in fresh WKY or SHR plasma were used to test for adhesion of light-weight donor red blood cell (RBC) by CD36. This form of RBC adhesion to macrophages was reduced after incubation in SHR compared WKY plasma. Analysis of the supernatant macrophage media by Western blot shows a higher level of CD36 extracellular protein fragments following exposure to SHR plasma compared to WKY. MMP inhibition in the SHR plasma compared to untreated plasma, served to increase the RBC adhesion to macrophages and decrease the number of receptor fragments in the macrophage media. In conclusion, these studies bring to light that plasma in the SHR model of metabolic disease has an unchecked MMP degrading activity which causes cleavage of a variety of membrane receptors, including CD36, which attenuates several cellular functions typical for the metabolic disease, including RBC adhesion to the scavenger receptor CD36. In addition to other cell dysfunctions chronic MMP inhibition restores CD36 in the SHR.

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Section: Introductionmentioning

confidence: 99%

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

Santamaria

Chen

Chow

et al. 2014

Microvascular Research

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“…Our results showed increased MMP activity in plasma and different peripheral tissues, which indicated a general increase in protease activity in SHRs. MMPs are primarily responsible for extracellular matrix remodeling, and recent studies demonstrated that increased MMP activity produces receptor dysfunction due to the extracellular cleavage of several membrane receptors in hypertension, such as insulin, VEGFR-2 and β 2 -adrenergic receptors [17][18][19][20][21]. The The scale bar is 500 μm.…”

Section: Discussionmentioning

confidence: 99%

“…Hypertension is a risk factor for mortality and morbidity [15,16]. Recent studies demonstrated that increased proteinase activity, including matrix metalloproteinases (MMPs), may be important in the loss of cellular function and end-organ damage in hypertension [17][18][19][20][21]. Clinical data support a role for plasma MMP-2 and MMP-9 levels as novel predictors of cardiovascular risk [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

“…In the same hypertensive rat strain, insulin receptor cleavage produces type II diabetes, vascular endothelial growth factor receptor 2 (VEGFR-2) cleavage induces endothelial apoptosis and reduces capillary density (rarefaction) [19][20][21]25]. 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: Introductionmentioning

confidence: 99%

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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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“…This pathology is the main cause of visual impairment in the population of economically developed countries [1][2][3][4]. It should be noted that even with the compensation of carbohydrate metabolism, the development of DR continues, so hyperglycemia is not the only factor in the development of retinopathy in diabetes [5][6][7][8][9]. To date, the key role of endothelial dysfunction in the occurrence and progression of DR has been proven [10,11].…”

Section: Introductionmentioning

confidence: 99%

Study of vasodilation processes

Sirman¹,

Savytskyi²

2019

J Educ Health Sport

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To date, the key role of endothelial dysfunction in the occurrence and progression of diabetes mellitus and diabetic retinopathy has been proven. The study was performed on white Wistar rats weighing 180-200 g. According to the tasks, the animals were divided into 7 groups. Our results indicate a violation of vasodilation on the 30th day of experimental diabetic retinopathy with subsequent progression of pathological changes on the 60th and 180 th day of the study, as evidenced by a decrease in the content of S-nitrosothiols in group 2 (p <0,001), most pronounced in the 3 rd stage. When analyzing the data of group № 3, it was found that the correction of the pathological condition with the help of hypoglycemic agents (correction of hyperglycemia, aflibercept, L-arginine and citicoline solution) more pronouncedly normalizes the content of the vasodilation marker compared to other groups of our experiment, which is pronounced in long-term correction-on 180 th day.

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The autodigestion hypothesis and receptor cleavage in diabetes and hypertension

Cited by 11 publications

References 94 publications

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

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

IGF-1 receptor cleavage in hypertension

Study of vasodilation processes

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