Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury

Forte, Amalia; Grossi, Mario; Turczyńska, Karolina M.; Svedberg, Kaj; Rinaldi, Barbara; Donniacuo, Maria; Holm, Anna; Baldetorp, Bo; Vicchio, Mariano; Feo, Marisa De; Santé, P; Galderisi, Umberto; Berrino, Liberato; Rossi, Francesco; Hellstrand, Per; Nilsson, Bengt‐Olof; Cipollaro, Marilena

doi:10.1016/j.ijcard.2013.04.153

Cited by 13 publications

(14 citation statements)

References 49 publications

(59 reference statements)

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“…The structure of the vascular wall is well maintained during polyamine depletion as demonstrated by unaltered endothelial expression of vWF and by expression of contractile phenotype marker proteins such as calponin and SM22α in the vessel media ex vivo and in vivo (present results, and Forte et al, ). At the mRNA level Cnn1 and Tagln , coding for these proteins, were increased whereas Spp1 , coding for the synthetic phenotype marker osteopontin (Wolak, ), was decreased by DFMO as well as by its combination with PTI‐1.…”

Section: Discussionsupporting

confidence: 73%

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Inhibition of Polyamine Uptake Potentiates the Anti‐Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells

Grossi

Phanstiel

Rippe

et al. 2015

Journal Cellular Physiology

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Increased vascular smooth muscle cell (VSMC) proliferation is a factor in atherosclerosis and injury-induced arterial (re) stenosis. Inhibition of polyamine synthesis by α-difluoro-methylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, attenuates VSMC proliferation with high sensitivity and specificity. However, cells can escape polyamine synthesis blockade by importing polyamines from the environment. To address this issue, polyamine transport inhibitors (PTIs) have been developed. We investigated the effects of the novel trimer44NMe (PTI-1) alone and in combination with DFMO on VSMC polyamine uptake, proliferation and phenotype regulation. PTI-1 efficiently inhibited polyamine uptake in primary mouse aortic and human coronary VSMCs in the absence as well as in the presence of DFMO. Interestingly, culture with DFMO for 2 days substantially (>95%) reduced putrescine (Put) and spermidine (Spd) contents without any effect on proliferation. Culture with PTI-1 alone had no effect on either polyamine levels or proliferation rate, but the combination of both treatments reduced Put and Spd levels below the detection limit and inhibited proliferation. Treatment with DFMO for a longer time period (4 days) reduced Put and Spd below their detection limits and reduced proliferation, showing that only a small pool of polyamines is needed to sustain VSMC proliferation. Inhibited proliferation by polyamine depletion was associated with maintained expression of contractile smooth marker genes. In cultured intact mouse aorta, PTI-1 potentiated the DFMO-induced inhibition of cell proliferation. The combination of endogenous polyamine synthesis inhibition with uptake blockade is thus a viable approach for targeting unwanted vascular cell proliferation in vivo, including vascular restenosis.

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Section: Discussionsupporting

confidence: 73%

“…Local application of DFMO inhibits smooth muscle proliferation without affecting the endothelial layer in rats exposed to a carotid lesion (Forte et al, ). This prior study, provided proof of principle for polyamines as a therapeutic target in this setting.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Polyamine Uptake Potentiates the Anti‐Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells

Grossi

Phanstiel

Rippe

et al. 2015

Journal Cellular Physiology

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“…Several such selective agents have been reported in the literature [12], [13] [14]–[16] [17]–[19] but with various limitations, e.g. lack of effect in vivo or difficulty in delivery.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screening Identifies Idarubicin as a Preferential Inhibitor of Smooth Muscle versus Endothelial Cell Proliferation

et al. 2014

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Intimal hyperplasia is the cause of the recurrent occlusive vascular disease (restenosis). Drugs currently used to treat restenosis effectively inhibit smooth muscle cell (SMC) proliferation, but also inhibit the growth of the protective luminal endothelial cell (EC) lining, leading to thrombosis. To identify compounds that selectively inhibit SMC versus EC proliferation, we have developed a high-throughput screening (HTS) format using human cells and have employed this to screen a multiple compound collection (NIH Clinical Collection). We developed an automated, accurate proliferation assay in 96-well plates using human aortic SMCs and ECs. Using this HTS format we screened a 447-drug NIH Clinical Library. We identified 11 compounds that inhibited SMC proliferation greater than 50%, among which idarubicin exhibited a unique feature of preferentially inhibiting SMC versus EC proliferation. Concentration-response analysis revealed this differential effect most evident over an ∼10 nM-5 µM window. In vivo testing of idarubicin in a rat carotid injury model at 14 days revealed an 80% reduction of intimal hyperplasia and a 45% increase of lumen size with no significant effect on re-endothelialization. Taken together, we have established a HTS assay of human vascular cell proliferation, and identified idarubicin as a selective inhibitor of SMC versus EC proliferation both in vitro and in vivo. Screening of larger and more diverse compound libraries may lead to the discovery of next-generation therapeutics that can inhibit intima hyperplasia without impairing re-endothelialization.

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“…We have published recently similar data obtained in vitro (on cultured primary rat SMCs and ECs) and in vivo (in a rat model of carotid arteriotomy), but based on the local application of an irreversible inhibitor [DFMO (α-diphluoromethylornithine)] of ODC (ornithine decarboxylase), a rate-limiting enzyme involved in polyamine biosynthesis [132]. The polyamines spermidine and spermine, and their precursor putrescine, are positively charged amines.…”

Section: Differential Pharmacological Effects On Smcs and Ecs: A Prommentioning

confidence: 92%

Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research

et al. 2014

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Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

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Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury

Abstract: Our data support the key role of polyamines in restenosis and suggest a novel therapeutic approach for this pathophysiological process.

Cited by 13 publications

References 49 publications

Inhibition of Polyamine Uptake Potentiates the Anti‐Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells

Inhibition of Polyamine Uptake Potentiates the Anti‐Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells

High-Throughput Screening Identifies Idarubicin as a Preferential Inhibitor of Smooth Muscle versus Endothelial Cell Proliferation

Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research

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