Apoptosis and Cell Proliferation After Porcine Coronary Angioplasty

Malik, Nadim; Francis, Sheila; Holt, Cathy M.; Gunn, Julian; Thomas, Graham L.; Shepherd, L; Chamberlain, Janet; Newman, Christopher M.; Cumberland, D.C.; Crossman, David C.

doi:10.1161/01.cir.98.16.1657

Cited by 133 publications

(92 citation statements)

References 30 publications

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“…Apoptosis has been described in both neointima, media and adventitia 39,40 with a maximum in neointima and media between 7 and 14 days after surgery 40 We demonstrate here that apoptosis was present at 7 days in Ad-␤Gal-infected arteries and was prevented by infusion of Ad-S2a.…”

Section: Discussionmentioning

confidence: 49%

Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Lipskaia

Monte

Capiod

et al. 2005

Circulation Research

127

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Abstract-Proliferation of vascular smooth muscle cells (VSMC) is a primary cause of vascular disorders and is associated with major alterations in Ca 2ϩ handling supported by loss of the sarco/endoplasmic reticulum calcium ATPase, SERCA2a. To determine the importance of SERCA2a in neointima formation, we have prevented loss of its expression by adenoviral gene transfer in a model of balloon injury of the rat carotid artery. Two weeks after injury, the intima/media ratio was significantly lower in SERCA2a-infected than in injured noninfected or injured ␤-galactosidaseinfected carotids (0.29Ϯ0.04 versus 0.89Ϯ0.19 and 0.72Ϯ0.14, respectively; PϽ0.05), and was comparable to that observed in control carotids (0.21Ϯ0.03). The pathways leading to proliferation were analyzed in serum-stimulated VSMC. Forced expression of SERCA2a arrested cell cycle at the G1 phase and prevented apoptosis. SERCA2a inhibits proliferation through inactivation of calcineurin (PP2B) and its target transcription factor NFAT (nuclear factor of activated T-cells) resulting in lowering of cyclin D1 and pRb levels. By using NFAT-competing peptide VIVIT, we showed that NFAT activity is strongly required to promote VSMC proliferation. In conclusion, we provide the first evidence that increasing SERCA2a activity inhibits VSMC proliferation and balloon injury-induced neointima formation. Key Words: vascular smooth muscle cell proliferation Ⅲ gene transfer Ⅲ SERCA2a Ⅲ calcium signaling Ⅲ nuclear factor of activated T-cells C ell hyper-proliferation is an important etiology factor of cardiovascular diseases such as primary atherosclerosis, restenosis, and vein-graft disease. 1,2 The neointimal vascular smooth muscle cell (VSMC) proliferation constitutes a primary cause of vascular disorders 1 but, despite increasing knowledge about the cell-cycle regulation of VSMC, the molecular mechanism governing VSMC proliferation remains elusive. Thus, identifying genetic modifiers of VSMC proliferation is a major focus in cardiovascular biology and medicine. 3 VSMCs have the ability to transition between quiescent differentiated and proliferating phenotypes. Acquisition of proliferating phenotype by VSMC is associated with alterations in Ca 2ϩ handling supported by modification of Ca 2ϩ transporter expression. 4 In quiescent VSMC, the Ca 2ϩ signal consists mainly of localized elementary calcium events. The global increase in Ca 2ϩ concentration is rapidly reduced by calcium pumps, keeping the cytoplasmic Ca 2ϩ concentration low. Spontaneous spark frequency decreases after activation of phosphoinositol-3 kinase (PI3K) and G protein-coupled receptors, probably attributable to inhibition of the ryanodine receptor (RyR). 6,7,14 -16 Several previous studies have suggested that SERCA2a is involved in the control of proliferation and growth: transgenic mice with only one allele of the ATP2a2 gene (SERCA2) develop numerous cancers of the upper digestive tract and skin, and cardiac hypertrophy 17,18 ; low levels of SERCA2a are associated with cardiac hypertrophy bot...

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Section: Discussionmentioning

confidence: 49%

Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Lipskaia

Monte

Capiod

et al. 2005

Circulation Research

127

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“…In contrast, chlamydial induction of foam cell formation, for example, can be promoted by chlamydial LPS alone (26). Proliferation of vascular cells has been characterized earlier as an integral part of atherosclerosis (27) and represents a general mechanism of arterial injury as observed in neointima formation after coronary angioplasty (28). The effects seen cannot be regarded as specific for C. pneumoniae or even bacteria.…”

Section: Discussionmentioning

confidence: 99%

Chlamydia pneumoniae infection promotes a proliferative phenotype in the vasculature through Egr-1 activation in vitro and in vivo

Rupp¹,

Hellwig-Bürgel²,

Wobbe³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Atherosclerosis is characterized by inflammation and proliferation of vascular cells. The intracellular bacterium Chlamydia (Chlamydophila) pneumoniae uses blood monocytes [peripheral blood mononuclear cells (PBMCs)] for dissemination, has been found to persist in atherosclerotic lesions, and has been implicated in atherogenesis by small GTPase activation and T lymphocyte recruitment. Infection of human coronary artery smooth muscle cells with C. pneumoniae significantly induced mRNA and protein for the angiogenic transcription factor Egr-1, resulting in enhanced coronary artery smooth muscle cell proliferation, which was reduced by transfection with small interfering RNA duplexes targeted at Egr-1 mRNA. These effects required viable chlamydiae and depended on p44͞42 mitogen-activated protein kinase activity but not on the p38 mitogen-activated protein kinase pathway. Postinfectious Egr-1 mRNA up-regulation in arterial vessels was confirmed ex vivo in a rat aortic ring model of focal vascular chlamydial infection. An in vivo model based on the injection of C. pneumoniae-infected PBMCs into mice confirmed Egr-1 mRNA up-regulation within 24 h of endovascular infection. Arterial injury from repeated direct chlamydial infections and cell-to-cell contact with C. pneumoniae-infected PBMCs might represent a chronic focus of proliferative activity linked to the media proliferation seen in advanced atherosclerosis. Overall, chlamydial infection induces a proliferative phenotype in vascular cells via transcription factor Egr-1 activation in vitro, ex vivo, and in vivo.atherosclerosis ͉ cell proliferation T he comprehension of the pathogenesis of atherosclerosis has changed fundamentally. Models suggesting atherogenesis as a static accumulation of lipid-loaded macrophages and adherent thrombocytes were expanded by a more dynamic view of the mechanisms involved (1). Inflammation and proliferation of vascular smooth muscle cells were established as the central pathomechanisms (2), suggesting that injurious stimuli other than the known risk factors may initiate and trigger atherosclerosis. Epidemiological studies indicated that persistent infectious agents like Chlamydia (Chlamydophila) pneumoniae or herpesviruses might be involved in perpetuating coronary artery disease. Although diagnostic assays have produced controversial results on its frequency in vascular infection, C. pneumoniae remains the only replicative pathogen that has been recovered from atherosclerotic lesions, where it seems to be deposited by infected circulating blood monocytes (3-6). Vascular C. pneumoniae infection has recently been linked to the inflammatory and procoagulatory component of atherosclerosis by demonstrating small GTPase-mediated NF-B activation (7). Chlamydial heat-shock protein (8) and a soluble factor derived from infected endothelial cells are known to trigger smooth muscle cell proliferation (9). The molecular mechanisms leading to postinfectious proliferation of vascular cells, however, are unknown, although the entry into and the pro...

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“…Thus, the inhibitory effect of RIP3 overexpression on neointimal formation is likely attributable to the increased apoptosis as well as suppressed proliferation of VSMCs. But it is still a matter of debate as to what is the impact of VSMC apoptosis on neointimal formation, as some evidence suggests that early apoptosis of medial VSMCs may increase late neointimal formation in vivo (53). Our preliminary data have demonstrated that overexpression of rRIP3 overtly attenuates VSMC migration (data not shown).…”

Section: Discussionmentioning

confidence: 79%

Receptor Interacting Protein 3 Suppresses Vascular Smooth Muscle Cell Growth by Inhibition of the Phosphoinositide 3-Kinase-Akt Axis

Geng

Lan

et al. 2010

Journal of Biological Chemistry

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Proliferation of vascular smooth muscle cells (VSMCs) is a primary mechanism underlying cardiovascular proliferative disorders. Phosphoinositide 3-kinase (PI3K)-Akt (or protein kinase B) axis has been assigned at the center of pathways that regulate cell proliferation. Here we demonstrate that enhanced PI3K-Akt signaling by mitogenic stimulation or arterial injury profoundly elevates expression of receptor interacting protein 3 (RIP3) in primary cultured rat VSMCs and in vivo and that the up-regulation of RIP3 leads to VSMC growth arrest and apoptosis via inhibiting the PI3K-Akt signaling pathway, thereby alleviating balloon injury-induced neointimal formation. Specifically, mitogenic stimulation with platelet-derived growth factor-BB or angiotensin II leads to a profound increase in RIP3 expression, which is abolished by inhibition of PI3K or Akt, and increased PI3K-Akt signaling by expression of a constitutively active PI3K mutant also elevates RIP3 expression. Importantly, adenoviral overexpression of RIP3 not only triggers apoptosis but also causes cell cycle arrest at G 1 /G 0 phases that is associated with suppressed Akt activation. In sharp contrast, RIP3 gene silencing enhances serum-and platelet-derived growth factorinduced cell proliferation and Akt activation. In vivo adenoviral gene delivery of rat RIP3 (rRIP3) increased apoptosis and reduced VSMC proliferation, thus, effectively alleviating balloon injury-induced neointimal formation. The growth-suppressive and pro-apoptotic effects are independent of rRIP3 Ser/Thr kinase activity, because overexpression of a kinase-inactive mutant of rRIP3, similar to its wild type, is sufficient to induce growth arrest and apoptosis. These findings reveal a novel growth-suppressive action of RIP3, marking RIP3 as an important factor to prevent excessive mitogenic stimulation-or injury-induced vascular smooth muscle cells hyperplasia.To maintain tissue homeostasis, eukaryotic cells must keep a balance of cell proliferation and cell death in response to various sources of injury or stress stimuli. Cell hyper-proliferation has long been considered as an important etiological factor of cardiovascular diseases and cancer. Vascular smooth muscle cells (VSMCs) 4 are normally maintained in a non-proliferative state in the arterial tunica media. But arterial injury, inflammation, or excessive mitogenic stimulation triggers transmigration of VSMCs from the media into the intima layer of the arterial wall, where the VSMCs proliferate and synthesize extracellular matrix proteins, resulting in expansion of the arterial intima, i.e. neointimal formation (1-3). Proliferation of neointimal VSMCs is the most common causes of severe cardiovascular diseases such as hypertension, ischemic heart disease, and subsequent myocardial infarction, strokes, and congestive heart failure (4).Multiple factors, including growth factors, neurohormones, inflammatory cytokines, and reactive oxygen species, have been implicated in vascular proliferative disorders. For instance, platelet-derived gr...

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Apoptosis and Cell Proliferation After Porcine Coronary Angioplasty

Abstract: These results suggest that the profile of apoptosis and proliferation after PTCA is regional and cell specific, and attempts to modulate either of these events for therapeutic benefit requires recognition of these differences.

Cited by 133 publications

References 30 publications

Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Chlamydia pneumoniae infection promotes a proliferative phenotype in the vasculature through Egr-1 activation in vitro and in vivo

Receptor Interacting Protein 3 Suppresses Vascular Smooth Muscle Cell Growth by Inhibition of the Phosphoinositide 3-Kinase-Akt Axis

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Apoptosis and Cell Proliferation After Porcine Coronary Angioplasty

Abstract: These results suggest that the profile of apoptosis and proliferation after PTCA is regional and cell specific, and attempts to modulate either of these events for therapeutic benefit requires recognition of these differences.

Cited by 133 publications

References 30 publications

Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Chlamydia pneumoniae infection promotes a proliferative phenotype in the vasculature through Egr-1 activation in vitro and in vivo

Receptor Interacting Protein 3 Suppresses Vascular Smooth Muscle Cell Growth by Inhibition of the Phosphoinositide 3-Kinase-Akt Axis

Contact Info

Product

Resources

About

Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat