Statins for the prevention of vein graft stenosis: a role for inhibition of matrix metalloproteinase-9

2002 ◽  
Vol 30 (2) ◽  
pp. 120-126 ◽  
Author(s):  
K. E. Porter ◽  
N. A. Turner
Keyword(s):  
Matrix Metalloproteinase ◽  
Intimal Hyperplasia ◽  
Therapeutic Potential ◽  
Matrix Metalloproteinase 2 ◽  
Neointima Formation ◽  
Graft Stenosis ◽  
The Matrix ◽  
And Migration ◽  
Proliferation And Migration

Saphenous vein (SV) grafts are commonly used to bypass coronary arteries that are diseased due to atherosclerosis. However, the development of intimal hyperplasia in such grafts can lead to patency-threatening stenosis and re-occlusion of the vessel. The proliferation and migration of smooth muscle cells (SMC) play key roles in the development of intimal hyperplasia, and an agent that inhibits both of these processes therefore has therapeutic potential. A prerequisite for SMC proliferation and migration in vivo is degradation of the basement membrane, achieved by secretion of the matrix-degrading gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9. Statins are cholesterol-lowering drugs that also have direct effects on SMC function. Here we report that neointima formation in organ-cultured human SV segments is inhibited by simvastatin, an effect that is associated with reduced MMP-9 activity. Additionally, our work shows that simvastatin not only inhibits proliferation, but importantly also inhibits invasion (migration through a matrix barrier), of cultured human SV SMC. Thus simvastatin treatment appears to inhibit neointima formation as a result of combined inhibition of SMC proliferation and invasion. The potential intracellular mechanisms by which statins affect SMC proliferation and migration, and thus attenuate intimal hyperplasia, are discussed, with particular emphasis on the role of MMP-9.

scholarly journals Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

2021 ◽  
Vol 22 (11) ◽  
pp. 5602
Author(s):  
Hyeon Young Park ◽  
Mi-Jin Kim ◽  
Seunghyeong Lee ◽  
Jonghwa Jin ◽  
Sungwoo Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Metabolic Reprogramming ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
And Migration ◽  
Proliferation And Migration

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

Empagliflozin impairs smooth muscle cell proliferation, accelerates endothelial regeneration, and prevents neointima formation by altered expression of the vasoactive peptide apelin

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Dutzmann ◽  
L.M Bode ◽  
L Korte ◽  
K Kalies ◽  
S Koch ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Injury ◽  
Blue Staining ◽  
Funding Source ◽  
Neointima Formation ◽  
And Migration ◽  
Vasoactive Peptide ◽  
Proliferation And Migration

Abstract Background Empagliflozin, an inhibitor of the sodium glucose co-transporter 2 (SGLT2), developed as an anti-diabetic agent exerts additional beneficial effects on heart failure outcomes in patients with type 2 diabetes mellitus at high cardiovascular risk. However, the effect of empagliflozin on vascular cell function and vascular remodeling processes remain largely elusive. Methods/Results Immunocytochemistry and immunoblotting revealed SGLT2 to be expressed in human diabetic and non-diabetic smooth muscle (SMC) and endothelial cells (EC) as well as in murine femoral arteries. In vitro, empagliflozin significantly reduced serum-induced proliferation and migration of human diabetic and non-diabetic SMCs in a dose-dependent manner without any toxic or apoptotic effects. In contrast, empagliflozin significantly increased the cell count and migrational capacity of human diabetic ECs, but not of human non-diabetic ECs. In vivo, therapeutic application of empagliflozin (225 mg/kg medicated diet) resulted in a significantly reduced number of Ki-67+ proliferating neointimal cells in response to femoral artery wire-injury in C57BL/6J mice. Empagliflozin furthermore prevented subsequent neointima formation (luminal stenosis 91.2% vs. 80.6% at 21 days; P<0.05). Comparable effects of empagliflozin were observed in a streptozocin-induced diabetic model of apolipoprotein E−/− mice. Conclusive to the in vitro-results, re-endothelialization was not significantly affected in C57BL/6 mice (non-reendothelialized distance 2.57 mm vs. 2.3 mm; P=0.07), but even significantly improved in diabetic mice after treatment with empagliflozin (3.1 mm vs. 2.58 mm; P<0.001) assessed by Evan's Blue staining 3 days after electric denudation of the murine carotid artery. Microarray analysis of human SMCs identified the vasoactive peptide apelin to be decisively regulated in response to empagliflozin treatment. Further pathway analysis exhibited apelin to prevent SMC proliferation by de-phosphorylation of Akt and to augment EC proliferation by phosphorylation of p38 MAPK. Conclusion These data document the functional impact of empagliflozin on vascular SMCs and ECs for the first time. Empagliflozin significantly reduces serum-induced proliferation and migration of SMCs in vitro and prevented neointima formation in vivo, while augmenting EC proliferation in vitro and re-endothelialization in vivo after vascular injury. Thus, empagliflozin holds promise to exert favorable effects on vascular healing, and to prevent neointima formation following vascular injury in diabetic and non-diabetic patients. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Hannover Medical School, Martin-Luther-University Halle-Wittenberg

scholarly journals Sonic hedgehog-dependent activation of adventitial fibroblasts promotes neointima formation

2017 ◽  
Vol 113 (13) ◽  
pp. 1653-1663 ◽  
Author(s):  
Jochen Dutzmann ◽  
Alexander Koch ◽  
Simona Weisheit ◽  
Kristina Sonnenschein ◽  
Laura Korte ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Neointima Formation ◽  
Adventitial Fibroblasts ◽  
Initial Activation ◽  
Functional Relevance ◽  
And Migration ◽  
Activated Fibroblasts ◽  
Proliferation And Migration

Abstract Aims Adventitial cells have been suggested to contribute to neointima formation, but the functional relevance and the responsible signalling pathways are largely unknown. Sonic hedgehog (Shh) is a regulator of vasculogenesis and promotes angiogenesis in the adult. Methods and results Here we show that proliferation of vascular smooth muscle cells (SMC) after wire-induced injury in C57BL/6 mice is preceded by proliferation of adventitial fibroblasts. Simultaneously, the expression of Shh and its downstream signalling protein smoothened (SMO) were robustly increased within injured arteries. In vitro, combined stimulation with Shh and platelet-derived growth factor (PDGF)-BB strongly induced proliferation and migration of human adventitial fibroblasts. The supernatant of these activated fibroblasts contained high levels of interleukin-6 and -8 and strongly induced proliferation and migration of SMC. Inhibition of SMO selectively prevented fibroblast proliferation, cytokine release, and paracrine SMC activation. Mechanistically, we found that PDGF-BB activates protein kinase A in fibroblasts and thereby induces trafficking of SMO to the plasma membrane, where it can be activated by Shh. In vivo, SMO-inhibition significantly prevented the proliferation of adventitial fibroblasts and neointima formation following wire-induced injury. Conclusions The initial activation of adventitial fibroblasts is essential for the subsequent proliferation of SMC and neointima formation. We identified SMO-dependent Shh signalling as a specific process for the activation of adventitial fibroblasts.

Abstract 332: Inhibition of the Enhancer of Zeste Homolog Family Mitigates Intimal Hyperplasia in Rat Carotid Arteries

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Mengxue Zhang ◽  
Bowen Wang ◽  
Go Urabe ◽  
Xudong Shi ◽  
Lian-Wang Guo
Keyword(s):  
Intimal Hyperplasia ◽  
Transcriptional Repression ◽  
Vascular Diseases ◽  
Inhibition Of Proliferation ◽  
Enhancer Of Zeste ◽  
Dual Inhibition ◽  
And Migration ◽  
Proliferation And Migration

Rationale: The enhancer of zeste homologs 1 and 2 (EZH1 and EZH2) are histone-lysine N-methyltransferases that modify histones by methylation which leads to transcriptional repression. It has recently been shown that EZH1 and EZH2 play an important role in various cancers. Whether they play a role in recurrent vascular diseases is not known. Objective: We assessed whether EZH1 and EZH2 are important contributors to the development of intimal hyperplasia (IH) and restenosis. Methods and Results: Following rat carotid balloon angioplasty, EZH2 showed highest expression at day 3 post procedure and then decreased at day 7 in injured arteries, as determined by Western blotting. Change of EZH1 is less prominent. Dual inhibition of EZH1 and EZH2 through peri-adventitial administration of a selective inhibitor, UNC-1999, effectively inhibited intimal hyperplasia, with ~40% reduction in the ratio of intima to media (I/M). Moreover, in cultured primary rat smooth muscle cells (SMCs) as well as MOVAS cells, pretreatment with 5μM UNC-1999 resulted in a 60% decrease in cell proliferation and ~80% reduction of migration that were stimulated by PDGF-BB. Simultaneous knockdown of EZH1 and EZH2, as well as knockdown of their shared scaffold protein(EED), led to effective inhibition of proliferation and migration of SMCs. However, knockdown of EZH2 alone did not recapitulate the effects of dual inhibition of EZH1 and EZH2. Conclusions: This study demonstrates that dual inhibition of EZH1 and EZH2, both histone modifiers, mitigates intimal hyperplasia in vivo and attenuates PDGF-BB stimulated SMC proliferation and migration in vitro.

scholarly journals Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells

2018 ◽  
Vol 115 (37) ◽  
pp. E8660-E8667 ◽  
Author(s):  
Abu Shufian Ishtiaq Ahmed ◽  
Kunzhe Dong ◽  
Jinhua Liu ◽  
Tong Wen ◽  
Luyi Yu ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Phenotypic Switching ◽  
Specific Gene ◽  
Neointima Formation ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic “off” state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases.

scholarly journals TGF-β Plays a Key Role in Morphogenesis of the Pancreatic Islets of Langerhans by Controlling the Activity of the Matrix Metalloproteinase MMP-2

1998 ◽  
Vol 143 (3) ◽  
pp. 827-836 ◽  
Author(s):  
Francisco Miralles ◽  
Tadej Battelino ◽  
Paul Czernichow ◽  
Raphael Scharfmann
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinase ◽  
Islets Of Langerhans ◽  
Neutralizing Antibody ◽  
Matrix Metalloproteinase 2 ◽  
Pancreatic Islets Of Langerhans ◽  
The Matrix ◽  
Vitro Model

Islets of Langerhans are microorgans scattered throughout the pancreas, and are responsible for synthesizing and secreting pancreatic hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association, first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017–1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-β1 positively controls both islet morphogenesis and MMP-2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF-β neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-β is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis.

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