Increased neointimal formation in cystathionine gamma-lyase deficient mice: Role of hydrogen sulfide in α5β1-integrin and matrix metalloproteinase-2 expression in smooth muscle cells

doi:10.1016/j.yjmcc.2011.12.004

Journal of Molecular and Cellular Cardiology

Volume 52, Issue 3, March 2012, Pages 677-688

https://doi.org/10.1016/j.yjmcc.2011.12.004 Get rights and content

Abstract

The physiological and pathological roles of hydrogen sulfide (H₂S) in the regulation of cardiovacular functions have been recognized. Vascular smooth muscle cells (SMCs) express cystathionine gamma-lyase (CSE) and produce significant amount of H₂S. Although growing evidence demonstated the anti-atherosclerotic effect of H₂S, less is known about the contribution of the endogenous CSE/H₂S pathway to the development of vascular remodeling. This study investigated the roles of the CSE/H₂S pathway on SMC migration and neoimtimal formation by using CSE knockout (KO) mice. SMCs and aortic explants isolated from CSE KO mice exhibited more migration and outgrowth compared with that from wild-type (WT) mice, and exogenously applied NaHS (a H₂S donor) at 100 μM significantly inhibited SMC migration and outgrowth. SMCs became more elongated and spread in the absence of CSE, and fibronectin significantly stimulated adhesion and migration of SMCs from CSE KO mice (KO–SMCs) in comparison with SMCs from WT mice (WT–SMCs). The expressions of α5- and β1-integrins were significantly higher in KO–SMCs, and functional blocking of α5β1-integrin effectively abrogated KO–SMC migration. CSE deficiency also enhanced matrix metalloproteinase-2 (MMP-2) expression, and the selective blocking of MMP-2 decreased KO–SMC migration. NaHS treatment decreased both the expressions of α5- and β1-integrins and MMP-2. We further found that the expressions of α5- and β1-integrins as well as MMP-2, were stimulated by fibronectin, and that the blockage of α5β1-integrin reduced but overexpression of α5β1-integrin induced MMP-2 expression in both WT–SMCs and KO–SMCs. We also noticed that CSE deficiency in mice led to increased neointima formation in carotid arteries 4 weeks after ligation, which were attenuated by NaHS administration. In conclusion, inhibition of SMC migration by H₂S may be a novel target for the treatment of vascular occlusive disorder.

Highlights

► Cystathionine gamma-lyase deficiency induces smooth muscle cell migration. ► H₂S inhibits the expressions of α5β1-integrin and MMP-2. ► Cystathionine gamma-lyase deficiency induces neointima formation in mice. ► H₂S attenuates neointima formation in mice.

Introduction

Hydrogen sulfide (H₂S) is emerging as a novel and important gasotransmitter in the cardiovascular system [1], [2], [3]. Vascular smooth muscle cells (SMCs) express cystathionine gamma-lyase (CSE) and produce a significant amount of H₂S [4], [5]. CSE-derived H₂S inhibits SMC proliferation and decreases vascular tone [1], [2]. Abnormal metabolism and functions of the CSE/H₂S pathway have been linked to various cardiovascular diseases, including atherosclerosis [6], [7]. Cystathionine beta-synthase (CBS) also has been consistently shown to produce H₂S in mammalian tissues with L-cysteine and/or homocysteine as the main substrate [2], [8]. The third enzyme 3-mercaptopyruvate sulfurtransferase was recently identified, which uses both L-cysteine and alpha-ketoglutarate as substrates along with cysteine aminotransferase to produce H₂S [9]. Although CBS and 3-mercaptopyruvate sulfurtransferase were reported to be involved in certain cardiovascular disorders, it is unclear yet whether both enzymes are expressed in SMCs.

Vascular neointimal formation is a common consequence of vascular lesions. In response to vascular injuries, SMCs migrate from the tunica media to the intima where they participate in neointima formation [10], [11]. The process of SMC migration is regulated by an array of signals. Prominent signals include the interaction of integrins with the surrounding extracellular matrix (ECM) as well as an altered expression of matrix-degrading proteases [12]. The ECM affects the functions of SMCs such as adhesion and spreading [13]. Integrins, known as αß-heterodimeric cell-surface receptors, are the linkage between the ECM and the intracellular signaling apparatus [14]. β1- and β3-integrins are upregulated after balloon catheter injury of the rat carotid artery, and antibody-mediated blockage of these subunits reduced SMC migration and neointimal formation [15], [16]. Studies with fibroblasts, keratinocytes, and melanoma cells have demonstrated that matrix metalloproteinase (MMP) production is regulated by feedback from the ECM through integrin receptor signaling [15], [17]. MMPs belong to a family of zinc-dependent endopeptidases capable of degrading all components of ECM and facilitate SMC migration [18]. Of the 20-odd MMPs, investigators have focused on MMP-2 and MMP-9 (gelatinases A and B) because both MMPs are secreted by SMCs, and they are capable of degrading most of the matrix and basement membrane [19]. Increased activities of both MMP-2 and MMP-9 have been identified in human atherosclerosis, in a rat arterial injury model, and during neointima formation in the human saphenous vein induced by surgical injury [20], [21]. The inhibition of MMP activity by various synthetic inhibitors of MMPs and intrinsic tissue inhibitors of MMPs (TIMPs) almost completely abolishes SMC migration into the neointima, which underscores its potential importance in the process of neointima formation [21].

The interaction of H₂S, integrins, and MMPs has been reported. Protein expressions of MMP-2 and MMP-9 were significantly higher in the brain of CBS knockout (KO) mice as compared to wild-type (WT) mice, and CBS KO mice supplemented with NaHS showed a significant decrease in MMP-2 and MMP-9 protein expressions in brain, suggesting the therapeutic potential of H₂S against hyperhomocysteinemia-increased microvascular permeability [22]. H₂S protected the heart against oxidative stress and adverse remodeling in chronic heart failure by mitigating the expressions of MMP-2 and − 9 [23]. In contrast, H₂S improved pulmonary artery collagen remodeling by stimulating MMP-13 expression in rats [24]. H₂S impaired keratinocyte cell adhesion by down-regulating β4-, α2-, and α6-integrins [25]. β1-integrin expression was significantly increased in the aorta of CSE KO mice compared with that of WT mice [4]. However, the effects of the CSE/H₂S system on integrins, MMPs and SMC migration have not been well characterized, and identifying the interaction between the CSE/H₂S system and SMC migration may provide new insight into the pathogenesis of neointimal formation in proliferative cardiovascular diseases.

In the present study, we demonstrated that CSE deficiency stimulated SMC migration and induced neointimal formation in a carotid artery ligated mouse model. H₂S treatment attenuated both SMC migration and neotintimal formation. The activation of α5β1-integrin and MMP-2 expression contributed to CSE deficiency-induced SMC migration.

Section snippets

Cell culture

SMCs from the mesenteric artery of WT mice and CSE KO mice were isolated and identified as previously described [4]. These SMCs were cultured in Dulbecco's modified Eagle's medium containing 10% supplemented fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin at 37 °C. The experiments were performed when the cells reached 70–80% confluence between passages 5 and 10. In all studies, cells were first incubated in the serum-free medium overnight and then cells were then harvested

CSE deficiency induced SMC adhesion and migration

To determine whether lack of CSE affects SMC migration and adhesion, a modified Boyden chamber chemotaxis assay was used. CSE deficiency significantly increased KO–SMC migration by 81.8 ± 4.5% compared with WT–SMCs in the absence of serum (Fig. 1a). The addition of serum induced both WT–SMC and KO–SMC migration with a greater effect on KO–SMCs (p < 0.05, Fig. 1a). To validate the in vitro data, we examined the ability of SMCs to migrate out of aortic explants isolated from WT and KO mice. SMC

Discussion

The physiological and pathological role of H₂S in the regulation of cardiovascular function has been recognized. H₂S directly activates the ATP-sensitive K⁺ channels and relaxes SMCs [35], improves mitochondrial function, and provides protection on cardiac myocytes [36], and appears to serve as an endothelium-derived relaxing factor [37]. There is also a growing body of evidence demonstrating the anti-atherosclerotic roles of H₂S. H₂S attenuates balloon injury-induced neointima lesion in rat

Disclosures

None declared.

Acknowledgment

This study was supported by operating grants from the Canadian Institutes of Health Research to G.Y and R.W. G.Y. was supported by a New Investigator award from the Heart and Stroke Foundation of Canada and a Maureen Andrew New Investigator award from the Heart and Stroke Foundation of Ontario.

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Enzymatic degradation of elastin by matrix metalloproteinases (MMPs) leads to the permanent dilation of aortic wall and constitutes the most prominent characters of aortic aneurysm and aging-related medial degeneration. Hydrogen sulfide (H₂S) as a gasotransmitter exhibits a wide variety of cardio-protective functions through its anti-inflammatory and anti-oxidative actions. Cystathionine gamma-lyase (CSE) is a main H₂S-generating enzyme in cardiovascular system. The regulatory roles of CSE/H₂S system on elastin homeostasis and blood vessel degeneration have not yet been explored. Here we found that aged CSE knockout mice had severe aortic dilation and elastic degradation in abdominal aorta and were more sensitive to angiotensin II-induced aortic elastolysis and medial degeneration. Administration of NaHS would protect the mice from angiotensin II-induced inflammation, gelatinolytic activity, elastin fragmentation, and aortic dilation. In addition, human aortic aneurysm samples had higher inflammatory infiltration and lower expression of CSE. In cultured smooth muscle cells (SMCs), TNFα-induced MMP2/9 hyperactivity and elastolysis could be attenuated by exogenously applied NaHS or CSE overexpression while further deteriorated by complete knockout of CSE. It was further found that H₂S inhibited MMP2 transcription by posttranslational modification of Sp1 via S-sulfhydration. H₂S also directly suppressed MMP hyperactivity by S-sulfhydrating the cysteine switch motif. Taken together, this study revealed the involvement of CSE/H₂S system in the pathogenesis of aortic elastolysis and medial degeneration by maintaining the inactive form of MMPs, suggesting that CSE/H₂S system can be a target for the prevention of age-related medial degeneration and treatment of aortic aneurysm.
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As a positive control, mice treated with 0.5 g/L NaHS had significantly higher polysulfides levels in the liver (Figure 2e). CSE is the main enzyme responsible for endogenous H2S production in the vasculature and Cse−/− mice have been shown to develop more IH.16,21,41 To study the impact of STS on restenosis independently of endogenous H2S production, we generated a new Cse−/− mouse line.
Intimal hyperplasia (IH) remains a major limitation in the long-term success of any type of revascularisation. IH is due to vascular smooth muscle cell (VSMC) dedifferentiation, proliferation and migration. The gasotransmitter Hydrogen Sulfide (H₂S), mainly produced in blood vessels by the enzyme cystathionine- γ-lyase (CSE), inhibits IH in pre-clinical models. However, there is currently no H₂S donor available to treat patients. Here we used sodium thiosulfate (STS), a clinically-approved source of sulfur, to limit IH.
Low density lipoprotein receptor deleted (LDLR^−/−), WT or Cse-deleted (Cse^−/−) male mice randomly treated with 4 g/L STS in the water bottle were submitted to focal carotid artery stenosis to induce IH. Human vein segments were maintained in culture for 7 days to induce IH. Further in vitro studies were conducted in primary human vascular smooth muscle cells (VSMCs).
STS inhibited IH in WT mice, as well as in LDLR^−/− and Cse^−/− mice, and in human vein segments. STS inhibited cell proliferation in the carotid artery wall and in human vein segments. STS increased polysulfides in vivo and protein persulfidation in vitro, which correlated with microtubule depolymerisation, cell cycle arrest and reduced VSMC migration and proliferation.
STS, a drug used for the treatment of cyanide poisoning and calciphylaxis, protects against IH in a mouse model of arterial restenosis and in human vein segments. STS acts as an H₂S donor to limit VSMC migration and proliferation via microtubule depolymerisation.
This work was supported by the Swiss National Science Foundation (grant FN-310030_176158 to FA and SD and PZ00P3-185927 to AL); the Novartis Foundation to FA; and the Union des Sociétés Suisses des Maladies Vasculaires to SD, and the Fondation pour la recherche en chirurgie vasculaire et thoracique.
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Hydrogen sulphide (H2S) is an endogenously produced gasotransmitter.3 Preclinical studies have shown that H2S has cardiovascular protective properties,4 including reduction of IH,5–7 possibly via decreased VSMC proliferation.6,8 However, there is currently no clinically approved H2S donor.9
Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H₂S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H₂S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H₂S. Here, it was hypothesised that zofenopril, due to H₂S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia.
Spontaneously hypertensive male Cx40 deleted mice (Cx40^–/–) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro.
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Similarly, SMCs isolated from CSE-KO mice exhibited more migration and outgrowth compared with that from WT mice, which was significantly inhibited by applying NaHS (100 μM) [177]. Brahma-related gene 1 (Brg1) can use the energy derived from hydrolysis of ATP to disrupt the chromatin architecture of target promoters [178,179]. Li et al. demonstrated that H2S inhibited VSMC proliferation by reducing the recruitment of Brg1 and proliferation-related gene promoter regions, including proliferating cell nuclear antigen (Pcna), neurotrophin 3 (Ntf3) and platelet-derived growth factor subunit A (Pdgfα) [180].
Atherosclerosis (AS), an important cause of high mortality of cardiovascular disease, involves numerous pathophysiological processes, including endothelial cell damage, oxidative stress, inflammation, lipid deposition, vascular smooth muscle proliferation and migration, macrophage-derived foam cell formation, and platelet aggregation, and seriously endangers human health and safe of life. Hydrogen sulfide (H₂S) was discovered as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO), and has been proposed to exert potentially significant effects in many physiological processes, especially in atherosclerosis. Compelling evidence suggests that malfunction of CSE/H₂S pathway and downregulation of endogenous H₂S level contribute to the pathogenesis of atherosclerosis, whereas exogenous supplementation of H₂S can ameliorate many of atherogenic processes. The current knowledge on the anti-atherogenic role of H₂S comes from the use of H₂S donors and CSE or CBS inhibitors, or another more accurate genetic technology, including gene knockout and gene therapy studies. Among them H₂S releasing donors have vast therapeutic potential in anti-atherosclerosis and are promising as one of the clinical strategies for atherosclerosis treatment. Based on the recent studies on therapeutic effects and mechanisms of H₂S donors, this review focuses on the most recent advances of therapeutic potential of H₂S donors in anti-atherosclerosis, especially synthetic organic donors, because sulfide salts can release H₂S rapidly and lead to various adverse effects. In addition, the future of this domain is prospected.

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Original articleIncreased neointimal formation in cystathionine gamma-lyase deficient mice: Role of hydrogen sulfide in α5β1-integrin and matrix metalloproteinase-2 expression in smooth muscle cells

Abstract

Highlights

Introduction

Section snippets

Cell culture

CSE deficiency induced SMC adhesion and migration

Discussion

Disclosures

Acknowledgment

Am J Pathol

J Surg Res

Int J Biochem Cell Biol

Neurochem Int

Lab Invest

J Biol Chem

Cell

Am J Pathol

Biochem Pharmacol

Trends Pharmacol Sci

Signaling pathways for the vascular effects of hydrogen sulfide

Curr Opin Nephrol Hypertens

Hydrogen sulfide in cell survival: a double-edged sword

Expert Rev Clin Pharmacol

Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter?

FASEB J

Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells

Cardiovasc Res

Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3

FASEB J

Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice

Arterioscler Thromb Vasc Biol

Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice

Circ Res

Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide

J Biochem

Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation

Circ Res

Origin of neointimal smooth muscle: we've come full circle

Arterioscler Thromb Vasc Biol

Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat

Circ Res

Matrix metalloproteinases and cardiovascular disease

Circ Res

Integrin beta1 subunit controls mural cell adhesion, spreading, and blood vessel wall stability

Circ Res

Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin

Arterioscler Thromb Vasc Biol

Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly

Circ Res

Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates

Cardiovasc Res

Original article
Increased neointimal formation in cystathionine gamma-lyase deficient mice: Role of hydrogen sulfide in α5β1-integrin and matrix metalloproteinase-2 expression in smooth muscle cells

Two's company, three's a crowd: can H₂S be the third endogenous gaseous transmitter?