Changes in cholesterol levels in the plasma membrane modulate cell signaling and regulate cell adhesion and migration on fibronectin

Ramprasad, O. G.; Srinivas, G.; Rao, K. Sridhar; Joshi, Powrnima; Thiery, Jean Paul; Dufour, Sylvie; Pande, Gopal

doi:10.1002/cm.20176

Cited by 73 publications

(62 citation statements)

References 61 publications

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“…Because cell migration is a coordinated process consisting of signaling and cytoskeletal rearrangement, our data suggest that resistin might enhance the interaction between extracellular matrix and actin fiber structuring during cell migration. The cytoplasmic tails of integrins are linked to actin cytoskeleton via a complex of anchoring proteins known as focal adhesion components (4), including FAK and paxillin; the association of paxillin with integrins markedly enhanced the rates of integrindependent phosphorylation of FAK and cell migration (19,33). Our finding that resistin significantly enhanced levels of phosphorylated paxillin might explain the increased phosphorylation of downstream kinases such as FAK in VSMCs.…”

Section: Discussionmentioning

confidence: 88%

Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin

Jiang¹,

Zhang²,

Zhang³

et al. 2009

American Journal of Physiology-Cell Physiology

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Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeletonrelated proteins were also detected. The results showed that Hcy (300 -500 M) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time-and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an ␣5␤1-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocytederived resistin, which provides further evidence of the adiposevascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.adipose-vascular interaction; insulin resistance; cytoskeleton

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Section: Discussionmentioning

confidence: 88%

Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin

Jiang¹,

Zhang²,

Zhang³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…The role of PCSK9 on cell migration has not been reported previously, although the effect of changes in cholesterol levels in the plasma membrane on cell adhesion and migration has been documented 30,31 . In particular, the activity of Rac-1 and Rho-A is sensitive to cholesterol levels and distribution in the plasma membrane 32 and statins, by depleting the intracellular cholesterol, affects the invasive morphology of breast cancer cells 33 .…”

Section: Discussionmentioning

confidence: 97%

“…In particular, the activity of Rac-1 and Rho-A is sensitive to cholesterol levels and distribution in the plasma membrane 32 and statins, by depleting the intracellular cholesterol, affects the invasive morphology of breast cancer cells 33 . Recruitment of integrins to focal adhesions and formation of focal adhesions at the leading edge of cells requires cholesterol 30,34,35 and the formation of specialized cholesterol-containing microdomains called caveolae 36 . Thus, it is tempting to speculate that the higher expression levels of LDLR, observed in SMCs PCSK9 -/-, could have been sufficient to alter the cholesterol membrane homeostasis and thus integrin recycling, focal adhesion formation, and lamellipodia protrusion to the leading edge of the cells and thus cell migration.…”

Section: Discussionmentioning

confidence: 99%

PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement

et al. 2016

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Proprotein convertase subtilisin kexin type 9 (PCSK9) is a keyregulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and co-localizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9-/-) and wild type (WT) littermate (PCSK9+/+) mice. Collared carotids of the PCSK9-/-mice showed less intimal thickening compared to WT mice (p<0.05), a decreased intimal media ratio (p<0.02) and tendency to higher lumen area. When compared with PCSK9-/-, carotid lesions of WT mice had a higher content of SMCs (p<0.05) and collagen (p<0.05). No difference in macrophage content was detected between the two groups. SMCs freshly isolated from PCSK9-/-, when compared to PCSK9+/+ cells, showed higher levels of the contractile markers α-smooth muscle actin (α-SMA; 2.24±0.36 fold; p<0.01) and myosin heavy chain II (MHC-II; 8.65±1.55 fold; p<0.01), and decreased levels of synthetic markers caldesmon (-54±14%; p<0.01). PCSK9-/-cells also showed in response to platelet-derived growth factor-BB (PDGF-BB) a slower proliferation rate, and impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9-/-SMCs, led to a downregulation of α-SMA (-56±2%; p<0.01) and significant induction of caldesmon (1.46±0.3 fold; p<0.05). Proliferation rate of SMCs PCSK9-/-was significantly lower compared to PCSK9 reconstituted cells. Taken together, the present results suggest that by sustaining SMC synthetic phenotype, proliferation and migration PCSK9 may play a pro-atherogenic role in the arterial wall. HighlightsIn response to perivascular manipulation, the neointimal formation is reduced in PCSK9 -/-mice PCSK9 directly regulates smooth muscle cell differentiation, proliferation and migrationThe reconstitution of PCSK9 expression in SMCs PCSK9 -/-determines a switch towards a synthetic phenotype and rescue the impaired proliferation and migration capacities of SMCs PCSK9 -/-SMCs PCSK9 -/-respond less efficiently to the proliferative and chemotactic action of PDGF-BB 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractProprotein convertase subtilisin kexin type 9 (PCSK9) is a key-regulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and colocalizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9 -/-) and wild type (WT) littermate (PCSK9 +/+ ) mice. Collared carotids of the PCSK9 -/-mice showed less intimal thickening compared...

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“…Both cholesterol and several SNAREs have been implicated in the molecular machinery that is responsible for the endocytic and exocytic trafficking of integrins. As such, the cholesterol content of the plasma membrane controls signaling events that are mediated by aVb3 integrins (Green et al, 1999), including focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) signaling pathways, and cell adhesion and migration on fibronectin-coated substrates (Ramprasad et al, 2007). In this context, the ability of SNAREs to bind cholesterol in specific cellular sites could contribute to the establishment of functional links between cholesterol and integrin localization and function.…”

Section: Golgi-localized Cholesterol Regulates Snare-dependent Integrmentioning

confidence: 99%

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

Enrich

Rentero

Hierro

et al. 2015

Journal of Cell Science

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The cell surface delivery of extracellular matrix (ECM) and integrins is fundamental for cell migration in wound healing and during cancer cell metastasis. This process is not only driven by several soluble NSF attachment protein (SNAP) receptor (SNARE) proteins, which are key players in vesicle transport at the cell surface and intracellular compartments, but is also tightly modulated by cholesterol. Cholesterol-sensitive SNAREs at the cell surface are relatively well characterized, but it is less well understood how altered cholesterol levels in intracellular compartments impact on SNARE localization and function. Recent insights from structural biology, protein chemistry and cell microscopy have suggested that a subset of the SNAREs engaged in exocytic and retrograde pathways dynamically 'sense' cholesterol levels in the Golgi and endosomal membranes. Hence, the transport routes that modulate cellular cholesterol distribution appear to trigger not only a change in the location and functioning of SNAREs at the cell surface but also in endomembranes. In this Commentary, we will discuss how disrupted cholesterol transport through the Golgi and endosomal compartments ultimately controls SNARE-mediated delivery of ECM and integrins to the cell surface and, consequently, cell migration.

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Changes in cholesterol levels in the plasma membrane modulate cell signaling and regulate cell adhesion and migration on fibronectin

Cited by 73 publications

References 61 publications

Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin

Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin

PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

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