Blockade of Connexin 43 Hemichannels Reduces Neointima Formation After Vascular Injury by Inhibiting Proliferation and Phenotypic Modulation of Smooth Muscle Cells

Song, Mingbao; Yu, Xin; Cui, Xiufang; Zhu, Guangxu; Zhao, Gang; Chen, Jianfei; Huang, Lan

doi:10.3181/0902-rm-80

Cited by 39 publications

(30 citation statements)

References 41 publications

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“…In support of this idea, recent studies have highlighted a potential role for connexin 43 hemichannels in regulating vascular smooth muscle cell phenotype in response to balloon injury and other mitogenic stimuli. 41,42 Further, our data suggest that the presence of both Wnt3a and TGF-b may have an additive effect on cell phenotype, as we observed their combined effects to be much greater than the effect of either protein individually.…”

Section: Discussionmentioning

confidence: 56%

“…28 It has previously been reported that connexin 43 expression is upregulated in smooth muscle cells in response to injury in rodent models and in early human atherosclerosis, situations in which elevated Wnt signaling has been reported 7,14 and in which increased extracellular matrix synthesis is well documented. 3,38 Reducing connexin 43 expression has been shown to inhibit lesion development in rodent models of atherosclerosis and acute vascular injury, [39][40][41] suggesting potential pro-atherogenic functions for gap junction communication. Our data suggest Wnt3a increases the expression of connexin 43 in vascular smooth muscle cells, and this increase in connexin 43 expression is associated with increased intercellular communication and matrix synthesis.…”

Section: Discussionmentioning

confidence: 99%

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WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Carthy

Luo

McManus

2012

Laboratory Investigation

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Evidence suggests a role for Wnt signaling in vascular wound repair and remodeling events. Despite this, very little is known about the effect of Wnt ligands on the structure and function of vascular cells. In this study, we treated vascular smooth muscle cells with 250 ng/ml of recombinant Wnt3a for 72 h and observed changes in the cell phenotype. Our data suggest Wnt3a completely alters the phenotype of vascular smooth muscle cells. The Wnt3a-treated cells appeared larger and had increased formation of stress fibers. These cells also had increased expression of the smooth muscle contractile proteins, calponin and smooth muscle a-actin, and contracted a collagen lattice faster than control cells. The Wnt3a-treated smooth muscle cells displayed increased extracellular matrix synthesis, as measured by collagen I and III mRNA expression, along with increased expression of MMP2 and MMP9, but decreased TIMP2 levels. The Wnt3a-induced change in cell phenotype was associated with increased expression of the gap junction protein connexin 43. Consistent with this, Wnt3a-treated smooth muscle cells displayed enhanced intercellular communication, as measured by the scrape-loading dye transfer technique. The canonical Wnt antagonist, dickkopf-related protein 1, completely reversed the contractile protein and connexin 43 expression seen in the Wnt3a-treated cells, suggesting these changes were dependent on canonical Wnt signaling. Collectively, this data suggest Wnt3a promotes a contractile and secretory phenotype in vascular smooth muscle cells that is associated with increased gap junction communication. Numerous studies have demonstrated that after arterial injury, vessel walls follow a response-to-injury pattern of wound healing leading to stenosis secondary to the neointimal accumulation of smooth muscle cells and extracellular matrix. 1-4 A number of soluble mediators released at the site of vascular injury act as molecular cues that guide smooth muscle cell responses during repair. 5,6 Growing evidence suggest a role for the Wnt family of secreted glycoproteins and their associated signaling pathways in regulating many of the processes involved in vascular wound repair and remodeling events. [7][8][9][10][11][12][13][14] However, the precise mechanisms and outcomes of Wnt signaling in such settings remain unclear. Moreover, the effect of specific Wnt family members on vascular cell phenotype remain undefined.The Wnt signaling pathway is best recognized for its role in the development of multi-cellular organisms, 15,16 and is critically involved in normal heart formation. 17 The Wnt family is comprised of 19 secreted glycoproteins that bind the Frizzled receptor and its co-receptor, lipoprotein receptorrelated proteins 5/6, to initiate an intracellular signaling cascade that controls the turnover of b-catenin. 18 In the absence of Wnt ligand, b-catenin is targeted for ubiquitinmediated degradation by the 26S proteasome. However, upon ligand stimulation, canonical Wnt signaling triggers a series of phosphorylation even...

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Carthy

Luo

McManus

2012

Laboratory Investigation

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“…As mentioned previously, the baseline diameter remained constant throughout our study, indicating that the decrease in FMD was not the result of a change in resting tone. Thus this attenuation effect of CBX on FMD could be attributed to the blockade of endothelial gap junctions (37).…”

Section: Discussionmentioning

confidence: 99%

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults

Lan

Hou

Yen

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Gap junctions play a key role in maintaining the functional integrity of the vascular wall. Using carbenoxolone (CBX) as a gap junction blocker, we aimed to assess the contribution of gap junctions in the vascular wall to flow-mediated vasodilatation (FMD) in healthy adults. Percentage FMD (%FMD) and circulating vasoactive molecules/activity, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), aldosterone, cortisol, plasma renin activity (PRA), and endothelin (ET-1) , were measured in 25 healthy volunteers (mean age: 30.1 Ϯ 5.4 yr; 14 males) before and after oral administration of CBX (100 mg). %FMD decreased after ingestion of CBX (9.71 Ϯ 3.1 vs. 3.40 Ϯ 2.0%; P Ͻ 0.0001). The levels of ANP, BNP, cortisol, and ET-1 remained stationary, while both PRA and aldosterone decreased (P Ͻ 0.005) after CBX ingestion. Blood pressure and heart rate were minimally changed by CBX. Inhibition of gap junctional communication by CBX impairs FMD in healthy persons, suggesting that physiologically, vascular gap junctions participate in the maintenance of FMD. CBX does not induce the release of vasoconstricting molecules or enhance vasoconstriction, suggesting that inhibition of gap junctional communication by CBX underlies the impairment of FMD. Therefore, administering CBX in FMD examination can be a way to follow the effect of gap junctions on endothelial function, but further work remains to verify the specificity of CBX effect. flow-mediated dilation; gap junctions; vasoactive molecules THE VASCULAR ENDOTHELIUM PLAYS a central role in the regulation of vasomotor tone, thrombogenecity, and inflammation (33). Endothelial dysfunction, an indicator of impairment of these regulatory mechanisms, is a systemic disorder and a key early event in the pathogenesis of atherosclerosis (29,44). In fact, endothelial dysfunction can be detected long before the appearance of structural atherosclerotic disease and is associated with increased cardiovascular risk (47). Accumulated data indicated that atherosclerotic cardiovascular disease also affects endothelial gap junctions, which are involved in maintaining functional integrity of the endothelium (21,22,48).Gap junctions are cell membrane protein channels made of connexins. Our previous study showed that downregulation of endothelial gap junctions is a common phenomenon in various disorders that induce and accelerate atherosclerosis (16), such as hypertension (23), hyperlipidemia (49), and diabetes (15) in cases where endothelial dysfunction exists. In addition, we (46) recently reported that in cultured endothelial cells, reduction of gap junctions per se leads to the development of endothelial dysfunction. However, all of this information comes from cell culture and animal experiments; thus, the contribution of gap junctions to the maintenance of endothelial function in humans remains unclear. To clarify the role of gap junctions, we hypothesized that gap junction blockade impairs flow-mediated vasodilatation (FMD), a clinically applicable examination for evaluat...

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“…In some experiments CBX did not alter connexin 43 hemichannel (Cx43Hc) conductance [125]. In another study CBX has been proven to disrupt hemichannel packing and aggregation in vivo [126], and CBX acts indirectly by intercalating into the cell membrane, altering the local lipid environment to hinder plaque formation [127].…”

Section: Gap Junction Channel Inhibitors (Fig 2)mentioning

confidence: 99%

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

Szentmiklósi¹,

Szentandrássy²,

Hegyi³

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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Blockade of Connexin 43 Hemichannels Reduces Neointima Formation After Vascular Injury by Inhibiting Proliferation and Phenotypic Modulation of Smooth Muscle Cells

Cited by 39 publications

References 41 publications

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

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Blockade of Connexin 43 Hemichannels Reduces Neointima Formation After Vascular Injury by Inhibiting Proliferation and Phenotypic Modulation of Smooth Muscle Cells

Cited by 39 publications

References 41 publications

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults

Chemistry, Physiology, and Pharmacology of &#946;.-Adrenergic Mechanisms in the Heart. Why are .&#946;-Blocker Antiarrhythmics Superior?

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Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?