Platelet Expression of Stromal Cell-Derived Factor-1 Is Associated with the Degree of Valvular Aortic Stenosis

Wurster, Thomas; Tegtmeyer, Roland; Rath, Dominik; Geisler, Tobias; Gawaz, Meinrad; Bigalke, Boris

doi:10.1371/journal.pone.0097405

Cited by 7 publications

(5 citation statements)

References 32 publications

(43 reference statements)

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“…Elevated systemic TGF-b1 is observed in AS, 18 and AS progression is associated with increased plasma levels of TGF-b1 in mice. 19 Because platelets are the major source of plasma TGF-b1, and platelet activation is observed in AS, [19][20][21][22][23] we hypothesized that platelet-released TGF-b1 may directly contribute to AS progression. To study AS progression, we first established an aggressive and robust mouse model (LDLR) that enhances spontaneous AS progression and high WSS across AV.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of platelet-derived TGF-β1 attenuates aortic stenosis progression in a robust murine model

et al. 2019

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Aortic stenosis (AS) is a degenerative heart condition characterized by fibrosis and narrowing of aortic valves (AV), resulting in high wall shear stress (WSS) across valves. AS is associated with high plasma levels of transforming growth factor-β1 (TGF-β1), which can be activated by WSS to induce organ fibrosis, but the cellular source of TGF-β1 is not clear. Here, we show that platelet-derived TGF-β1 plays an important role in AS progression. We first established an aggressive and robust murine model of AS, using the existing Ldlr−/−Apob100/100 (LDLR) breed of mice, and accelerated AS progression by feeding them a high-fat diet (HFD). We then captured very high resolution images of AV movement and thickness and of blood flow velocity across the AV, using a modified ultrasound imaging technique, which revealed early evidence of AS and distinguished different stages of AS progression. More than 90% of LDLR animals developed AS within 6 months of HFD. Scanning electron microscopy and whole-mount immunostaining imaging of AV identified activated platelets physically attached to valvular endothelial cells (VEC) expressing high phosphorylated Smad2 (p-Smad2). To test the contribution of platelet-derived TGF-β1 in AS, we derived LDLR mice lacking platelet TGF-β1 (TGF-β1platelet-KO-LDLR) and showed reduced AS progression and lower p-Smad2 and myofibroblasts in their AV compared with littermate controls fed the HFD for 6 months. Our data suggest that platelet-derived TGF-β1 triggers AS progression by inducing signaling in VEC, and their subsequent transformation into collagen-producing-myofibroblasts. Thus, inhibiting platelet-derived TGF-β1 might attenuate or prevent fibrotic diseases characterized by platelet activation and high WSS, such as AS.

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Section: Introductionmentioning

confidence: 99%

Inactivation of platelet-derived TGF-β1 attenuates aortic stenosis progression in a robust murine model

et al. 2019

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“…Surface expression of SDF-1α on platelets is a prospective biomarker in ischemic events [12]. The SDF-1α expression level on platelets is elevated in patients with acute myocardial infarction [18], acute coronary syndrome [19,20], coronary artery disease [21], valvular aortic stenosis [22], and congestive heart failure [23]. …”

Section: Introductionmentioning

confidence: 99%

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation

et al. 2017

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Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3β at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-β-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gβ and 4.0% of PI3Kβ, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.

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“…The association between shear stress and hemostatic activation has been demonstrated in vitro and in vivo in various clinical conditions, severe aortic stenosis being one of the best documented. Increased levels of sCD40L or sGPVI 14,15 in conjunction with a reduction of surface GPIba or GPVI, 16 platelet-derived chemokines 17 and serotonin 18 in platelet-free plasma, or of circulating platelet-derived microparticles [19][20][21] and platelet-monocyte aggregates 22 in whole blood have been reported in these patients. Platelet generation of eicosanoids resulting from the oxidative transformation of arachidonic acid through cyclooxygenase 1 (COX-1) and lipoxygenase (LOX) pathways is an early response to platelet activation.…”

Section: Discussionmentioning

confidence: 99%

“…12-HETE (ng/mL) median [IQ ] 9 . 0 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] 2.6 [1.5-3.9] <10 3…”

Section: Discussionunclassified

“…7 [1.9-7.3] 0.7 [0. 35 25 0.25 CD63 surface exposure (MFI) on resting platelets, median [IQ 26 [20][21][22][23][24][25][26][27][28] 23 0.70 CD62-P MFI fold-increase on stimulated platelets in PRP vs. resting platelets, median [IQ ] CRP 10 µg/mL 23 26 0.56 TRAP 50 µM 4 [2][3][4][5][6][7][8][9][10][11][12] 16 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] 0.07 CD63 MFI fold-increase on stimulated platelets in PRP vs. resting platelets CRP 10 µg/mL 14 [8][9][10][11][12][13][14][15][16]…”

Section: Discussionmentioning

confidence: 99%

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Platelet Activation Is Limited during Transcatheter Aortic Valve Implantation in Patients on Aspirin Monotherapy and without per Procedural Clinical Complications

Dumonteil

Levade

Garcia

et al. 2019

TH Open

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Transcatheter aortic valve implantation (TAVI) is an established treatment option for symptomatic patients with severe aortic valve stenosis (AS). During and early after the procedure, both ischemic events (predominantly stroke) and bleedings remain prevalent. The optimal antithrombotic regimen is still debated. Single- versus dual-antiplatelet therapy is associated with a lower rate of severe bleeding, without difference in thrombotic complications. Although platelets have been empirically targeted, little is known on their contribution to these events primarily related to embolization of thrombotic material and tissue-derived debris from the wounded aortic valve and large vessels. The objective of this study was to assess local platelet activation in blood sampled in the ascending aorta immediately before and within minutes postimplantation. A series of 18 patients with AS on monotherapy with aspirin successfully underwent TAVI with the self-expandable Medtronic CoreValve by transfemoral route. No clinical thrombotic complication occurred at 30-day follow-up. Compared with patients with stable coronary artery disease unscathed of AS and similarly treated by low-dose aspirin, AS patients displayed a chronic state of platelet activation before TAVI, assessed in venous blood using various biomarkers. However, per procedure, in aortic blood, no change occurred between the two time points in the plasma levels of serotonin or 12-lipoxgenase products, or membrane exposure of granule markers CD62-P and CD63. Our results suggest that local acute platelet activation is limited during TAVI on monotherapy with aspirin.

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Platelet Expression of Stromal Cell-Derived Factor-1 Is Associated with the Degree of Valvular Aortic Stenosis

Cited by 7 publications

References 32 publications

Inactivation of platelet-derived TGF-β1 attenuates aortic stenosis progression in a robust murine model

Inactivation of platelet-derived TGF-β1 attenuates aortic stenosis progression in a robust murine model

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation

Platelet Activation Is Limited during Transcatheter Aortic Valve Implantation in Patients on Aspirin Monotherapy and without per Procedural Clinical Complications

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