Comparative Genetics of Atherosclerosis and Restenosis: Exploration With Mouse Models

Wang, Xiaosong; Paigen, Beverly

doi:10.1161/01.atv.0000022201.18709.a1

Cited by 24 publications

(16 citation statements)

References 23 publications

(21 reference statements)

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“…The neointimal thickness in response to injury was determined by measuring the intima/media (I/M) area ratio throughout the entire injured segment starting from the junction between the internal and external left carotid branches. In agreement with previous reports (31,32), injury induced a marked increase in intimal hyperplasia in wild-type mice as observed 3 weeks after injury ( Figure 5, A and B). Interestingly, the I/M ratio was markedly enhanced in PPARα -/-mice,whereas it was drastically decreased in PPARα +/+ mice treated with fenofibrate, whose action in mice requires PPARα expression (33, 34) ( Figure 5, A and B).…”

Section: Figuresupporting

confidence: 93%

“…In agreement with the in vitro proliferation assays performed in mSMCs (Supplemental Figure 1), PPARα deficiency also provoked hyperplasia in C57BL/6J mice (Supplemental Figure 2), a strain reported to be more resistant to hyperplasia formation after carotid injury (31,32).…”

Section: Figuresupporting

confidence: 85%

“…The in vivo role of PPARα in the control of SMC proliferation was next examined by using a mechanical carotid artery injury mouse model (30) in Sv/129 mice, a strain highly susceptible to intimal hyperplasia (31). The neointimal thickness in response to injury was determined by measuring the intima/media (I/M) area ratio throughout the entire injured segment starting from the junction between the internal and external left carotid branches.…”

Section: Figurementioning

confidence: 99%

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PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Gizard¹,

Amant²,

Barbier³

et al. 2005

J. Clin. Invest.

148

133

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Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARα is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARα controls SMC cell-cycle progression at the G 1 /S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16 INK4a (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARα activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia. Moreover, PPARα activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARα inhibits SMC proliferation through p16. Thus, the PPARα/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.

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Section: Figuresupporting

confidence: 93%

Section: Figuresupporting

confidence: 85%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Gizard¹,

Amant²,

Barbier³

et al. 2005

J. Clin. Invest.

148

133

View full text Add to dashboard Cite

show abstract

“…3,143,144 Despite the procedural challenges, these two models, using inbred and genetically modified mouse models, can provide insight into the pathophysiology of atherosclerosis and mechanisms of neointimal hyperplasia and restenosis following vascular injury. 65,99,205 Rats have been used extensively since the 1960s as models for the evaluation of the vascular response to injury and smooth muscle cell proliferation using a variety of injurious stimuli. Although rat models have historically been limited by the same, size-related challenges as those encountered in mouse models, technical advances allow deployment of specially designed or commercially manufactured stents in the carotid artery or aorta, respectively (Fig.…”

Section: Rodentsmentioning

confidence: 99%

Preclinical Models of Restenosis and Their Application in the Evaluation of Drug-Eluting Stent Systems

Perkins

2010

Vet Pathol

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Coronary arterial disease (CAD) is the leading cause of death in the United States, the European Union, and Canada. Percutaneous coronary intervention (PCI) has revolutionized the treatment of CAD, and it is the advent of drug-eluting stent (DES) systems that has effectively allayed much of the challenge of restenosis that has plagued the success of PCI through its 30-year history. However, DES systems have not been a panacea: There yet remain the challenges associated with interventions involving bare metallic stents as well as newly arisen concerns related to the application of DES systems. To effectively address these novel and ongoing issues, animal models are relied on both to project the safety and efficacy of endovascular devices and to provide insight into the pathophysiology underlying the vascular response to injury and mechanisms of restenosis. In this review, preclinical models of restenosis are presented, and their application and limitation in the evaluation of device-based interventional technologies for the treatment of CAD are discussed.Keywords restenosis, stent, animal models, coronary artery disease Coronary artery disease (CAD) is the progressive accumulation of atherosclerotic plaque within the lumen of a coronary artery, with the typical result being luminal narrowing, reduced compliance of the vessel wall, and either a gradual reduction or a dramatic and sudden loss of blood supply to the myocardium. It is the leading cause of death in the United States, the European Union, and Canada, singly accounting for the death of 1 in 5 Americans. 117,185 In treatment options for symptomatic CAD, percutaneous coronary intervention (PCI) is the foremost modality, being based on the nonsurgical placement of a bare metallic scaffold, or stent, to prop open the artery to regain patency. However, there are drawbacks to coronary stenting, with restenosis being the Achilles' heel, accounting for a rate of failure up to 15 to 25%.18,124 Drug-eluting stents (DESs) have revolutionized PCI by effectively reducing restenosis rates to the single digits over standard bare metallic stents.DES systems combine mechanical and pharmacological approaches to assuage one or more events in the cascade that results in restenosis. These combination products consist of an intravascular scaffolding device that presents or releases single or multiple bioactive agents or pharmaceuticals into the bloodstream and arterial wall. Traditional DESs have consisted of a platform (stent), a carrier (usually a polymer), and an antirestenotic agent that is delivered locally to avert the need for high, systemically administered doses. The fundamental goal of the DES is to restore lumen patency while curtailing the diseased vessel's innate and often exuberant response to the implanted foreign material (stent) and to stent-induced injury. Despite the success of current DESs at achieving these goals, concerns have surfaced with their accruing clinical use. Such concerns pertain to vascular healing and late stent thrombosis, biocompat...

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“…Evaluation of murine strain differences has clearly shown gene-based variability for many vascular phenomena, 15 such as atherosclerosis, 20 arterial remodeling, 21 and stroke. 22 This report supports a hypothesis of different mechanisms for neointimal development operating under arterial-injury vs vein-graft conditions.…”

Section: Discussionmentioning

confidence: 99%

Mouse Strain Differential Neointimal Response in Vein Grafts and Wire-Injured Arteries

Cooley

2007

Circ J

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eointimal hyperplasia is a complication of both balloon angioplasty 1,2 and bypass vein grafting. [3][4][5] Experimental studies in mouse models have indicated several possible sources for the neointimal cells, 6 including circulating (pluripotent) cells with arterial wire/ballooninjury 7,8 and some vein graft models, 9,10 and predominantly local cells with arterial cuff injury 11 and in a modified vein graft model. 12 These differences suggest that more than 1 mechanism may be responsible for neointimal hyperplasia, depending on the initiating cause.In a recent report, Kuhel et al 13 identified mouse strain differences in the neointimal response to simulated balloon injury in the carotid artery, so the present study was done to evaluate neointimal formation after both vein grafting and arterial wire injury, using 2 mouse strains with highly disparate neointimal responses under arterial injury: 13 C57Bl/6 mice which show a low neointimal response, and FVB mice, which have a greater neointimal response. MethodsThe animal protocol was approved by the institutional Animal Care and Use Committee and was in accordance with NIH and AALAC guidelines. Male C57Bl/6 and FVB mice (Harlan Sprague-Dawley, Indianapolis, IN, USA), 8-12-weeks-old, were anesthetized with pentobarbital Circulation Journal Vol.71, October 2007Circ J 2007; 71: 1649 -1652 (Received April 11, 2007 revised manuscript received May 24, 2007; accepted July 2, 2007 Background Neointimal development is seen clinically after both vein grafting and balloon catheterization, but may not represent the same pathology under these 2 conditions. This study compared the degree of neointimal hyperplasia after vein grafting or arterial-injury grafts in 2 strains of mice: C57Bl/6 and FVB. Methods and Results Jugular vein branches were interpositioned as grafts in the femoral artery of syngenicmatched mice, with graft harvest at 30 days. Wire-injured carotid arteries were grafted to the carotid arteries of syngenic-matched mice, with graft harvest at 14 days. Histomorphometry revealed no strain differences in vein grafts in the extent of position-dependent neointimal thickening or lumen cross-sectional area. Both strains showed significantly thicker neointima and less lumen area at the proximal graft site (vs the mid-graft; p<0.05). In contrast, a significantly greater neointimal thickness was found in the wire-injured carotid grafts of FVB mice vs those of C57Bl/6 mice (p<0.05).Conclusions Neointimal formation shows a vessel-dependent, strain-dependent difference, with greater arterial neointimal thickening in FVB mice. These data suggest that different mechanisms operate for arterial-injury-vs vein-graft-associated neointimal development and that the difference has a genetic basis. (Circ J 2007; 71: 1649 -1652)

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Comparative Genetics of Atherosclerosis and Restenosis: Exploration With Mouse Models

Cited by 24 publications

References 23 publications

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Preclinical Models of Restenosis and Their Application in the Evaluation of Drug-Eluting Stent Systems

Mouse Strain Differential Neointimal Response in Vein Grafts and Wire-Injured Arteries

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