Heparin inhibits proliferation of myometrial and leiomyomal smooth muscle cells through the induction of alpha-smooth muscle actin, calponin h1 and p27

Horiuchi, Akiko; Nikaido, Toshio; Zhai, Yali; Ito, Kazuko; Orii, Ayaka; Fujii, Shingo

doi:10.1093/molehr/5.2.139

Cited by 36 publications

(25 citation statements)

References 37 publications

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“…30 These data suggest that heparin inhibition of SMC proliferation probably involves several different pathways. Our study revealed that the CDK inhibitor p27 plays a critical role in mediating the antiproliferative property of heparin on hypoxia-induced pulmonary hypertension and remodeling, but p21 does not.…”

Section: Discussionmentioning

confidence: 88%

“…Heparin inhibition of SMC proliferation has been associated with several factors including the suppression of c-fos and c-myc, 26 inhibition of the EGF receptor, 27 nitric oxide synthesis, 28 protein kinase activity, 29 modulation of cytosolic calcium, 30 inhibition of the Na ϩ /H ϩ exchanger, 19,25 as well as an increase in p21 11 and p27. 30 These data suggest that heparin inhibition of SMC proliferation probably involves several different pathways.…”

Section: Discussionmentioning

confidence: 99%

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Cyclin-Dependent Kinase Inhibitor p27 ^Kip1 , But Not p21 ^WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

Quinn

Garg

et al. 2005

Circulation Research

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Abstract-Heparin has growth inhibitory effects on pulmonary artery smooth muscle cell (PASMC) in vitro and in vivo.However, the mechanism has not been fully defined. In this study, we investigated the role of cyclin-dependent kinase inhibitors, p21 WAF1/cip1 (p21) and p27 Kip1 (p27), in the inhibitory effect of heparin on PASMC proliferation in vitro and on hypoxia-induced pulmonary hypertension in vivo using p21 and p27-null mice. In vitro, loss of the p27 gene negated the inhibitory effect of heparin on PASMC proliferation, but p21 was not critical for this inhibition. In vivo, heparin significantly inhibited the development of hypoxia-induced pulmonary hypertension and remodeling, as evidenced by decreased right ventricular systolic pressure, ratio of right ventricular weight to left ventricle plus septum weight, and percent wall thickness of pulmonary artery, in p21 ϩ/ϩ , p21 Ϫ/Ϫ , p27 ϩ/ϩ , and p27 ϩ/Ϫ , but not in p27 Ϫ/Ϫ mice. We also observed that hypoxia decreased p27 expression significantly in mouse lung, which was restored by heparin. Heparin inhibited Ki67 proliferative index in terminal bronchial vessel walls in p27 ϩ/ϩ and p27 ϩ/Ϫ , but not in p27 Ϫ/Ϫ mice exposed to hypoxia. Therefore, we conclude that the cyclin-dependent kinase inhibitor p27, but not p21, is required for the inhibition of hypoxic pulmonary vascular remodeling by heparin. Kip1 Ⅲ p21 WAF1/cip1 Ⅲ heparin Ⅲ pulmonary hypertension Ⅲ hypoxia Ⅲ mouse H eparin, a glycosaminoglycan, has been used as an anticoagulant for more than 50 years. 1 Besides anticoagulation, heparin has a variety of other biological activities, such as regulation of lipid metabolism, control of cell attachment to various proteins in the extracellular matrix, binding with acid and basic fibroblast growth factors, and inhibition of vascular smooth muscle cell (SMC) proliferation. 2 An important pathological feature of pulmonary hypertension is increased medial thickening of the pulmonary artery attributable to hypertrophy and hyperplasia of pulmonary artery SMC (PASMC). 3,4 Our previous studies have shown that antiproliferative heparins significantly inhibit pulmonary vascular remodeling induced by hypoxia in rodents 5-7 and PASMC proliferation in culture. 8 -10 Other investigators also have reported that heparin inhibits PASMC proliferation in vitro and in vivo. 8,11 To date, however, the mechanism by which heparin inhibits PASMC proliferation has not been elucidated.The balance between cell proliferation and cell quiescence is regulated by a variety of cell cycle modulators. Cyclindependent kinase (CDK) is a major regulator of the transition between the phases of the cell cycle. 12 Cyclin/CDK complexes are composed of a regulatory subunit, cyclin, and an active kinase subunit, CDK. The cyclin/CDK complexes are controlled by both positive and negative regulators. 13 p21 WAF1/cip1

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitor p27 ^Kip1 , But Not p21 ^WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

Quinn

Garg

et al. 2005

Circulation Research

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“…18 Overexpression of CNN1 could suppress SMC proliferation and neointima formation. 19,20 The X-box-binding protein 1 (XBP1) was originally identified as a stress-inducible transcription factor in both invertebrate and vertebrate cells, and essential for cell survival under stress conditions. [21][22][23] Under ER stress conditions, XBP1 mRNA undergoes unconventional splicing through an ER-resident kinase that possesses ribonuclease activity, the inositol-requiring enzyme 1 α (IRE1α).…”

mentioning

confidence: 99%

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

Zeng

Yang

et al. 2015

ATVB

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Objective-Smooth muscle cell (SMC) migration and proliferation play an essential role in neointimal formation after vascular injury. In this study, we intended to investigate whether the X-box-binding protein 1 (XBP1) was involved in these processes. Approach and Results-In vivo studies on femoral artery injury models revealed that vascular injury triggered an immediate upregulation of XBP1 expression and splicing in vascular SMCs and that XBP1 deficiency in SMCs significantly abrogated neointimal formation in the injured vessels. In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor β and the inositolrequiring enzyme 1α. The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). XBP1s directed the transcription of mir-1274B that targeted CNN1 mRNA degradation. Proteomic analysis of culture media revealed that XBP1s decreased transforming growth factor (TGF)-β family proteins secretion via transcriptional suppression. TGF-β3 but not TGF-β1 or TGF-β2 attenuated XBP1s-induced CNN1 decrease and SMC proliferation. Conclusions-This study demonstrates for the first time that XBP1 is crucial for SMC proliferation via modulating the platelet-derived growth factor/TGF-β pathways, leading to neointimal formation. under stress conditions. [21][22][23] Under ER stress conditions, XBP1 mRNA undergoes unconventional splicing through an ER-resident kinase that possesses ribonuclease activity, the inositol-requiring enzyme 1 α (IRE1α). 24 Our recent studies and reports from other groups showed that physiological stimuli such as vascular endothelial cell growth factor could trigger XBP1 splicing in an ER stress response-independent manner. [25][26][27][28] In endothelial cells (ECs), XBP1 splicing plays diverse roles, including cell proliferation, 26 autophagy response, 29 and apoptosis. 30 In SMCs, bone morphogenetic protein-2 was reported to activate XBP1 splicing, 31 but the exact role of XBP1 in SMCs still remains unclear. In this study, we demonstrated that XBP1 splicing is crucial in PDGF-BB-induced SMC proliferation and contributes to neointima formation after vascular injury. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Vascular Injury Increased XBP1 Expression and SplicingIn response to vascular injury, vascular SMCs will be activated undergoing migration, proliferation, and apoptosis. 32 To test whether XBP1 was involved in SMC activation, femoral artery injury model was introduced into the right side of C57Bl/6 mice. The injured vessels were harvested at day 1, and day 3 post surgery, whereas the left uninjured vessels were collected as control. Double immunofluorescence staining with anti-α SMC actin and antispliced XBP1 (XBP1s) or unspliced XBP1 (XBP1u) antibodies were performed on the cryo-sections. As shown in Figure 1A, low levels of XBP1s and XBP1u were detected in the uninjure...

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“…Heparin acts as an anticoagulant and is thought to stimulate angiogenesis [8]. Heparin proteoglycan, released by activated mast cells, inhibits the proliferation of smooth muscle cells in arterial tunica media and uterine myometrium [9,10].…”

Section: Brief Characteristics Of the Mast Cell And Its Role For Smoomentioning

confidence: 99%

“…It was demonstrated by [9] the inhibitory effect of heparin on human myometrium proliferation, suggesting that it could induce the differentiation of uterine smooth muscle cells and to influence tissue remodelling and reconstruction in different physiological and pathophysiological events.…”

Section: Heparinmentioning

confidence: 99%

Structure and Function of Smooth Muscle with Special Reference to Mast Cells

Vodenicharov¹

2012

Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues - From Molecules to Humans

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Heparin inhibits proliferation of myometrial and leiomyomal smooth muscle cells through the induction of alpha-smooth muscle actin, calponin h1 and p27

Cited by 36 publications

References 37 publications

Cyclin-Dependent Kinase Inhibitor p27 ^Kip1 , But Not p21 ^WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

Cyclin-Dependent Kinase Inhibitor p27 ^Kip1 , But Not p21 ^WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

Structure and Function of Smooth Muscle with Special Reference to Mast Cells

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Heparin inhibits proliferation of myometrial and leiomyomal smooth muscle cells through the induction of alpha-smooth muscle actin, calponin h1 and p27

Cited by 36 publications

References 37 publications

Cyclin-Dependent Kinase Inhibitor p27 Kip1 , But Not p21 WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

Cyclin-Dependent Kinase Inhibitor p27 Kip1 , But Not p21 WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

Structure and Function of Smooth Muscle with Special Reference to Mast Cells

Contact Info

Product

Resources

About

Cyclin-Dependent Kinase Inhibitor p27 ^Kip1 , But Not p21 ^WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice

Cyclin-Dependent Kinase Inhibitor p27 ^Kip1 , But Not p21 ^WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice