Effect of heparin on vascular smooth muscle cells. I. Cell metabolism

Castellot, John J.; Cochran, David L.; Karnovsky, Morris J.

doi:10.1002/jcp.1041240105

Cited by 216 publications

(124 citation statements)

References 23 publications

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“…Additionally, heparin might act intracellularly after being taken up by vascular smooth muscle cells [24,25]. A putative target of the intracellular action of heparin is the phosphoinositide-related calcium signalling.…”

Section: Discussionmentioning

confidence: 99%

Effect of heparin on proliferation and signalling in BC3H‐1 muscle cells

Vannucchi¹,

Pasquali²,

Fiorelli

et al. 1990

FEBS Letters

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We studied binding and growth inhibitory properties of different glycosaminoglycans in growing and differentiated BC3H-I muscle cells. Heparin (10 pg/ml) and heparan sulfate (10 ,ug/ml) significantly inhibited DNA synthesis in growing and differentiated cells, as monitored by PH]thymidine incorporation. Binding of heparin to BC3H-1 cells was specific and time-dependent. Heparan sulfate was the only glycosaminoglycan able to displace PH]heparin (I&,, 3.2 x lo-' M), although it was lo-fold less effective than heparin itself (IC,,, 3.6 x lo-* M). Scatchard analysis revealed the existence of high-alBnity heparin binding sites (K,,, 5 x lo-* M). Furthermore, heparin inhibited serum-induced stimulation of inositol lipid turnover. Taken together, these results indicate that heparin inhibits BC3H-1 cell growth by interacting with the cell surface, possibly disrupting the flow of growth factor-related mitogenic signalling.

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Section: Discussionmentioning

confidence: 99%

Effect of heparin on proliferation and signalling in BC3H‐1 muscle cells

Vannucchi¹,

Pasquali²,

Fiorelli

et al. 1990

FEBS Letters

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“…4 Briefly, the abdominal segment of the aorta was removed and the fascia cleaned away under a dissecting microscope. The aorta was cut longitudinally and small pieces of the media were carefully stripped from the vessel wall.…”

Section: Cell Culturementioning

confidence: 99%

“…4 Several studies point to the possibility that heparin blocks VSMC and mesangial cell proliferation via alterations in mitogenic signal transduction pathways.…”

mentioning

confidence: 99%

“…3 Heparin suppresses VSMC and mesangial cell proliferation while most other cells are unaffected. 4 Several studies point to the possibility that heparin blocks VSMC and mesangial cell proliferation via alterations in mitogenic signal transduction pathways. [5][6][7] Heparin binds to specific, saturable high-affinity binding sites on VSMC and is internalized by receptor-mediated endocytosis.…”

mentioning

confidence: 99%

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Heparin Inhibits Phosphorylation and Autonomous Activity of Ca2+/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle Cells

Mishra-Gorur

Singer

Castellot

2002

The American Journal of Pathology

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Vascular smooth muscle cell (VSMC) hyperproliferation is a characteristic feature of both atherosclerosis and restenosis seen after vascular surgery. A number of studies have shown that heparin inhibits VSMC proliferation in vivo and in culture. To test our hypothesis that heparin mediates its antiproliferative effect by altering Ca 2؉ regulated pathways involved in mitogenic signaling in VSMC, we analyzed the effect of heparin on multifunctional Ca 2؉ /calmodulin dependent protein kinase II (CaM kinase II) which is abundantly expressed in VSMC. Using activity assays, radioactive labeling, and immunoprecipitation it was found that heparin inhibits the overall phosphorylation of the ␦-subunit of CaM kinase II which is consistent with inhibition of autophosphorylation-dependent, Ca 2؉ /calmodulin-independent CaM kinase II activity. This effect was less evident in heparinresistant cells, consistent with a role for CaM kinase II in mediating the antiproliferative effect of heparin. Diseases of the heart and blood vessels are the leading cause of death in the United States and are responsible for almost half the deaths recorded each year. Most of these are due to atherosclerosis and its ensuing complications, which include hypertension, myocardial infarction, and gangrene. Hyperplasia of vascular smooth muscle cells (VSMC) is the hallmark of early atherogenesis and is considered the major cause of the high failure rate of vascular surgical procedures such as angioplasty, coronary artery bypass grafts, and heart transplants.1 The severity and prevalence of the problems associated with VSMC hyperplasia have provided the impetus to develop and characterize inhibitors of VSMC proliferation.Heparin and heparan sulfates are one such class of VSMC proliferation inhibitors.2 Work in our laboratory and by others has supported the antiproliferative role of heparin in animals and in culture systems.3 Heparin suppresses VSMC and mesangial cell proliferation while most other cells are unaffected. 4 Several studies point to the possibility that heparin blocks VSMC and mesangial cell proliferation via alterations in mitogenic signal transduction pathways.5-7 Heparin binds to specific, saturable high-affinity binding sites on VSMC and is internalized by receptor-mediated endocytosis. 8 Heparin has also been shown to selectively block the PKC pathway of mitogenic signaling as well as the phosphorylation and activation of MAPK.5,9 This is followed by a rapid down-regulation of mRNA levels of genes involved in growth regulation (eg, c-fos, c-jun, myb, and myc), thus blocking cells in the G 1 phase of the cell cycle.10 Despite these studies a causeeffect relationship has not yet been established.An important aspect of cellular signaling involves Ca 2ϩ mobilization in response to various stimuli. Calcium regulates a number of important functions in cells including proliferation, migration, contraction, and transcription, and the ability of heparin to block calcium transients in SMC has been appreciated for more than a decade. Several stu...

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“…43,46 Growth-arrested SMCs in cell culture are 50-100 times more sensitive to the antiproliferative effects of heparin than are exponentially growing cells in culture. 44 Thus, it seems adequate and important to start with LMWH treatment before SMCs are activated by the vessel wall injury caused by PTCA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.

et al. 1992

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Background. The proliferative response induced by balloon angioplasty is known to be an important factor in the development of restenosis after successful coronary angioplasty.Methods and Results. To study the effects of low-molecular-weight heparin (LMWH) on cellular proliferation after experimental balloon angioplasty, LMWH (3.9 kd, 400 anti-Xa units/kg/day) was given to 20 male New Zealand White rabbits. After an intimal fibromuscular plaque was induced by electrical stimulation in the right carotid artery, LMWH was applied during the 7 days after balloon dilatation. As the control group, 20 other rabbits underwent balloon angioplasty without application of LMWH. The vessels were excised 3, 7, 14, and 28 days after balloon treatment. During the final 18 hours before the rabbits were killed, bromodeoxyuridine was applied. Intimal wall thickness increased from 13±5 cell layers (preangioplasty control group) to 20±6 cell layers in the LMWH-treated group at 28 days (p<0.05). In contrast, histological examination of control animals 28 days after angioplasty revealed a significant increase to 35±+15 cell layers (p<0.01). Immunohistological quantification showed a significant increase (p<0.001) of cells undergoing DNA synthesis at 3 (10.2±4.2%) and 7 (7.7±4.8%) days after balloon dilatation in control animals. In contrast, at 3 and 7 days after balloon treatment, the percentage of cells undergoing DNA synthesis in LMWH-treated rabbits was lower (3 days, 2.7±1.8%; 7 days, 1.9+0.3%) than the corresponding untreated controls but showed a significant increase (p<0.01) compared with the preangioplasty controls. The differences between the two groups were statistically significant, however (3 days, p<0.01; 7 days, p<0.05). As early as 14 days after angioplasty, the extent of

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Effect of heparin on vascular smooth muscle cells. I. Cell metabolism

Cited by 216 publications

References 23 publications

Effect of heparin on proliferation and signalling in BC3H‐1 muscle cells

Effect of heparin on proliferation and signalling in BC3H‐1 muscle cells

Heparin Inhibits Phosphorylation and Autonomous Activity of Ca2+/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle Cells

Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.

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