MMP-1 and MMP-9 regulate epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

Rao, Velidi H.; Kansal, Vikash; Stoupa, Samantha; Agrawal, Devendra K.

doi:10.1002/phy2.224

Cited by 51 publications

(53 citation statements)

References 48 publications

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“…The cells from the second to fifth passage were used. The phenotype and the homogeneity of isolated smooth vessel cells were confirmed by positive staining for smooth muscle ␣-actin and caldesmon, as previously reported (8,18,45).…”

Section: Methodsmentioning

confidence: 73%

“…The carotid plaques from patients undergoing carotid endarterectomy were collected. The classification of the carotid plaques as unstable or stable from S and AS patients, respectively, was accordingly made to the criteria previously reported by us (8,45). Briefly, the carotid plaques were clinically classified by the surgeon as S from the history and clinical evaluation of the patients, including frequent plaque rupture, fibrous cap thinning, and fibrous cap foam-cell infiltration compared with those in AS patients.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the carotid plaques were clinically classified by the surgeon as S from the history and clinical evaluation of the patients, including frequent plaque rupture, fibrous cap thinning, and fibrous cap foam-cell infiltration compared with those in AS patients. The symptoms also included hemispheric transient ischemic attacks, amaurosis fugax, or stroke (8,45). The information on the categorization (S and AS plaque) of carotid stenosis was provided to laboratory investigators in an anonymous manner.…”

Section: Methodsmentioning

confidence: 99%

“…An established method developed in this laboratory was used to isolate VSMCs from carotid plaques (8,18,45). Briefly, the medial layer was homogenized, digested with trypsin, followed by digestion with collagenase type IA from Clostridium histolyticum (C2674, Sigma, St. Louis, MO) and the pellet was suspended in smooth muscle cell medium (ScienCell, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

“…However, the involvement of p38-MAPK and JNK-MAPK in EGF-mediated collagen loss in atherosclerotic plaques is poorly understood. Recently, we reported that EGF induces collagen loss involving EGFR and matrix metalloproteinases (MMPs), especially MMP-1 and MMP-9, in isolated vascular smooth muscle cells (VSMCs) from vulnerable carotid plaques (45).…”

Section: This Study Provides a Mechanistic Insight Into The Role Of Ementioning

confidence: 99%

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Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

Rao

Rai

Stoupa

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Rao VH, Rai V, Stoupa S, Agrawal DK. Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. Am J Physiol Heart Circ Physiol 309: H1075-H1086, 2015. First published August 7, 2015 doi:10.1152/ajpheart.00378.2015.-Although degradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be involved in symptomatic (S) carotid plaques in atherosclerosis, the mechanisms of MMP expression are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from S plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. Inhibitors of p38-MAPK and JNK-MAPK signaling pathways downregulated the expression of MMP-1 and MMP-9. In addition, we examined whether v-ets erythroblastosis virus E26 oncogene homologue 1 (Ets-1), an important regulator of different genes, is involved in destabilizing S plaques in patients with carotid stenosis. We demonstrate that EGF induces Ets-1 expression and decreases interstitial and basement membrane collagen in vascular smooth muscle cells (VSMCs) from patients with carotid stenosis. Increased expression of MMP-1 and -9 and decreased collagen mRNA transcripts were also found in Ets-1-overexpressed VSMCs. Transfection with both dominant-negative form of Ets-1 and small interfering RNA blocked EGF-induced MMP-1 and -9 expressions and increased the mRNA transcripts for collagen I (␣ 1) and collagen III (␣1) in S compared with asymptomatic (AS) carotid plaques. Inhibitors of p38-MAPK (SB202190) and JNK-MAPK (SP600125) signaling pathways decreased the expression of Ets-1, MMP-1, and MMP-9 and increased collagen type I and III expression in EGF-treated VSMCs. This study provides a mechanistic insight into the role of Ets-1 in the plaque destabilization in patients with carotid stenosis involving p38-MAPK and JNK signaling pathways. carotid plaque; collagen types I and III; epidermal growth factor; matrix metalloproteinases; v-ets erythroblastosis virus E26 oncogene homologue 1; vascular smooth muscle cells NEW & NOTEWORTHY This study provides a mechanistic insight into the role of Ets-1 regulated EGF induced collagen loss involving p38-MAPK and JNK signaling pathways in human carotid plaques with carotid stenosis. Selective blockade of Ets-1 and EGF receptor may be a novel strategy and promising target for treating unstable and vulnerable plaques.ATHEROSCLEROSIS IS A COMPLEX disease with coronary thrombus leading to stroke and is the major cause of morbidity and mortality throughout the world (8, 24). The matrix accumulation and degradation in the extracellular matrix (ECM) may determine the outcome of plaque stability (1). Proteases produced by the cellular components of the plaque are thought to be mainly responsible for thinning of the plaque cap and the development of myocardial infarction and stroke. Inflammatory cytokines (tumor necrosis factor-␣ and interleukin-1) and growth factors [epidermal growth factor ...

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Section: Methodsmentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: This Study Provides a Mechanistic Insight Into The Role Of Ementioning

confidence: 99%

See 3 more Smart Citations

Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

Rao

Rai

Stoupa

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Attenuation of aquaporin‐3 and epidermal growth factor receptor expression and activation in systemic sclerosis dermal fibroblasts

Farhadi

Mahmoudi

Rahmani

et al. 2018

Journal Cellular Physiology

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Objectives Impaired wound healing and skin dehydration are the mainstay of systemic sclerosis (SSc) cutaneous manifestations. Aquaporin‐3 (AQP3) has a pivotal role in skin hydration and wound healing. Epidermal growth factor receptor (EGFR) activation is impaired in SSc fibroblasts. It is unclear whether AQP3 downregulation or epidermal growth factor (EGF) signaling are the primary points of dysregulation in SSc patients. Methods Skin punch biopsies were obtained from 10 SSc patients and 10 healthy subjects. The mRNA and/or protein expression levels of AQP3, EGFR/p‐EGFR, matrix metalloproteinase‐1/2/9 (MMP‐1/2/9), and tissue inhibitors of metalloproteinase‐1 (TIMP1) at baseline and after EGF and transforming growth factor‐β1 (TGF‐β1) treatment was evaluated in extracted fibroblasts using real‐time polymerase chain reaction and western blot analysis. Results SSc fibroblasts expressed lower AQP3 and EGFR, compared with normal fibroblasts. Normal fibroblasts increased AQP3 expression in response to EGF whereas AQP3 expression had no change in EGF‐treated‐SSc fibroblasts. Likewise, EGFR was activated in response to EGF in the normal group but not SSc group. Baseline expression of MMP‐1/2/9 and TIMP1 was not different between SSc and controls. EGF treatment did not result in alteration of any MMPs expression in either of the groups. Combination treatment resulted in a significant upregulation of MMP‐1 in normal fibroblasts compared with SSc fibroblasts, while in SSc fibroblasts MMP‐9 expression was upregulated in response to treatment with TGF‐β1 only. Conclusion Downregulation of AQP3 expression in SSc fibroblasts may be related to reduced EGFR expression and activation. TGF‐β1 (alone or in combination with EGF) only can upregulate AQP3 expression in SSc fibroblasts so, TGF‐β1 affect MMP‐1 and MMP‐9 just in SSc fibroblasts.

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MMP-2 and MMP-14 Silencing Inhibits VEGFR2 Cleavage and Induces the Differentiation of Porcine Adipose-Derived Mesenchymal Stem Cells to Endothelial Cells

Almalki

Valle

Agrawal

2017

Stem Cells Translational Medicine

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The molecular mechanisms that control the ability of adipose‐derived mesenchymal stem cells (AMSCs) to remodel three‐dimensional extracellular matrix barriers during differentiation are not clearly understood. Herein, we studied the expression of matrix metalloproteinases (MMPs) during the differentiation of AMSCs to endothelial cells (ECs) in vitro. MSCs were isolated from porcine abdominal adipose tissue, and characterized by immunopositivity to CD44, CD90, CD105, and immunonegativity to CD14 and CD45. Plasticity of AMSCs was confirmed by multilineage differentiation. The mRNA transcripts for MMPs and Tissue Inhibitor of Metalloproteinases (TIMPs), and protein expression of EC markers were analyzed. The enzyme activity and protein expression were analyzed by gelatin zymography, enzyme‐linked immunosorbent assay (ELISA), and Western blot. The differentiation of AMSCs to ECs was confirmed by mRNA and protein expressions of the endothelial markers. The mRNA transcripts for MMP‐2 and MMP‐14 were significantly increased during the differentiation of MSCs into ECs. Findings revealed an elevated MMP‐14 and MMP‐2 expression, and MMP2 enzyme activity. Silencing of MMP‐2 and MMP‐14 significantly increased the expression of EC markers, formation of capillary tubes, and acetylated‐low‐density lipoprotein uptake, and decreased the cleavage of vascular endothelial growth factor receptor type 2 (VEGFR2). Inhibition of VEGFR2 significantly decreased the expression of EC markers. These novel findings demonstrate that the upregulation of MMP2 and MMP14 has an inhibitory effect on the differentiation of AMSCs to ECs, and silencing these MMPs inhibit the cleavage of VEGFR2 and stimulate the differentiation of AMSCs to ECs. These findings provide a potential mechanism for the regulatory role of MMP‐2 and MMP‐14 in the re‐endothelialization of coronary arteries following intervention. Stem Cells Translational Medicine 2017;6:1385–1398

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MMP-1 and MMP-9 regulate epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

Cited by 51 publications

References 48 publications

Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

Attenuation of aquaporin‐3 and epidermal growth factor receptor expression and activation in systemic sclerosis dermal fibroblasts

MMP-2 and MMP-14 Silencing Inhibits VEGFR2 Cleavage and Induces the Differentiation of Porcine Adipose-Derived Mesenchymal Stem Cells to Endothelial Cells

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