Central Role of PKCβ in Neointimal Expansion Triggered by Acute Arterial Injury

Andrassy, Martin; Белов, Д. В.; Harja, Evis; Zou, Yu; Leitges, Michael; Katus, Hugo A.; Nawroth, Peter P.; Yan, Shi Du; Schmidt, Ann Marie; Yan, Shi‐Fang

doi:10.1161/01.res.0000156903.37007.d1

Cited by 23 publications

(49 citation statements)

References 39 publications

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“…In fact, these molecules differentially regulate the ␣ 1 -AR-mediated contraction of smooth muscle cells in arteries (39). Similarly, in neointimal formation in the vascular injury model, these molecules were implicated in the signaling pathway (4,30). However, the implication and synergism of these molecules in ␣ 1 -AR-mediated neointimal formation remain uncertain.…”

Section: Discussionmentioning

confidence: 99%

Blockade of both α_1A- and α_1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Hosoda¹,

Hiroyama²,

Sanbe³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionmentioning

confidence: 99%

Blockade of both α_1A- and α_1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Hosoda¹,

Hiroyama²,

Sanbe³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…28 Vascular tissues were pooled from at least 4 animals, and total RNA was extracted by use of Trizol reagent (Life Technologies). Total RNA was reverse transcribed to cDNA by use of the TaqMan Reverse Transcription Reagents kit (Applied Biosystems) according to the manufacturer's protocol.…”

Section: Rna Extraction and Real-time Pcrmentioning

confidence: 99%

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Zhu

Xue

Zhao

et al. 2011

ATVB

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Objective-Restenosis after angioplasty remains a major clinical problem. Prostaglandin E 2 (PGE 2 ) plays an important role in vascular homeostasis. The PGE 2 receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. Methods and Results-Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2ϩ/ϩ) and EP2 gene-deficient (EP2Ϫ/Ϫ) mice. In EP2ϩ/ϩ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2Ϫ/Ϫ mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2Ϫ/Ϫ mice than in those of EP2ϩ/ϩ mice. Activation and overexpression of EP2 attenuated PDGF-BB-elicited cell proliferation and migration, induced G 1 3 S-phase arrest and reduced PDGF-BB-stimulated extracellular signal-regulated kinase phosphorylation in EP2ϩ/ϩ VSMCs. Conclusion-These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty. (Arterioscler Thromb Vasc Biol. 2011;31:1739-1747.)Key Words: angioplasty Ⅲ eicosanoids Ⅲ prostaglandins Ⅲ receptors Ⅲ restenosis P ercutaneous transluminal coronary angioplasty (PTCA) has been widely used for treating coronary atherosclerosis. However, many patients undergoing PTCA experience postangioplasty restenosis. 1 Although new devices for dilatation of stenosed arteries have lowered the incidence of acute complications, restenosis remains a major obstacle in the long-term outcome of PTCA interventions. 2 Restenosis is defined as the healing response of the arterial wall to mechanical injury and consists of 2 main processes: neointimal hyperplasia (smooth muscle migration/proliferation and extracellular matrix deposition) and vessel remodeling. 3 Platelet-derived growth factor-BB (PDGF-BB), an important growth factor released from platelets and leukocytes, plays a critical role in intimal hyperplasia after vascular injury. 4,5 An enormous amount of research has elucidated the molecular pathways involved in neointimal formation and vascular remodeling after vascular injury and has greatly advanced our understanding of the mechanisms contributing to the pathogenesis of restenosis. 6 -8 These efforts have led to many new strategies for effective prevention and treatment options for restenosis.Prostaglandin E 2 (PGE 2 ), a major arachidonic acid metabolite, is produced in the vasculature via a mechanism dependent on cyclooxygenase (COX) and prostaglandin E synthase. PGE 2 has important roles in the regulation of blood pressure, inflammatory response, immune response, an...

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“…In addition to its direct tumor effects, PKCh activation has been associated with pathologic angiogenesis in cancer (9), inflammation (10), and diabetes (11). Vascular endothelial growth factor (VEGF) receptor activation leads to PKChdependent endothelial cell proliferation.…”

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confidence: 99%

Inhibition of Protein Kinase Cβ by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer

Spalding¹,

Watson²,

Davis³

et al. 2007

Clinical Cancer Research

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Purpose: Aberrant activation of protein kinase Ch (PKCh) by pancreatic cancer cells facilitates angiogenesis and tumor cell survival. Targeting PKCh with enzastaurin, a well-tolerated drug in clinical trials, would be expected to radiosensitize pancreatic tumors through direct antitumor and antivascular effects. Experimental Design: We tested the hypothesis that enzastaurin radiosensitizes pancreatic cancer cells in culture and in vivo through inhibition of PKCh. We analyzed pancreatic cancer xenografts for growth delay and microvessel density after treatment with enzastaurin, radiation, or both.We determined the effect of radiation and enzastaurin on glycogen synthase kinase 3h, a mediator of cell death in culture and in vivo. Results: At concentrations attained in patients, enzastaurin reduced levels of active PKCh measured by phosphorylation at Thr 500 in culture and in xenografts. Enzastaurin alone did not affect pancreatic cancer cell survival, proliferation, or xenograft growth. However, enzastaurin radiosensitized pancreatic cancer cells in culture by colony formation assay. Enzastaurin alone decreased microvessel density of pancreatic cancer xenografts without appreciable effects on tumor size. When combined with radiation, enzastaurin increased radiation-induced tumor growth delay with a corresponding decrease in microvessel density. Enzastaurin inhibited radiation-induced phosphorylation of glycogen synthase kinase 3h at Ser 9 in pancreatic cancer cells in culture and in tumor xenografts, suggesting a possible mechanism for the observed radiosensitization. Conclusions: Enzastaurin inhibits PKCh in pancreatic cancer cells in culture, enhancing radiation cytotoxicity. Additional antivascular effects of enzastaurin were observed in vivo, resulting in greater radiosensitization. These results provide the rationale for a clinical trial in locally advanced pancreatic cancer combining enzastaurin with radiation.

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Central Role of PKCβ in Neointimal Expansion Triggered by Acute Arterial Injury

Cited by 23 publications

References 39 publications

Blockade of both α_1A- and α_1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Blockade of both α_1A- and α_1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Inhibition of Protein Kinase Cβ by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer

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Central Role of PKCβ in Neointimal Expansion Triggered by Acute Arterial Injury

Cited by 23 publications

References 39 publications

Blockade of both α1A- and α1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Blockade of both α1A- and α1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Inhibition of Protein Kinase Cβ by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer

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Blockade of both α_1A- and α_1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Blockade of both α_1A- and α_1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice