P2y12 Receptor Promotes Pressure Overload–Induced Cardiac Remodeling via Platelet-Driven Inflammation in Mice

Wu, Lujin; Zhao, Fujie; Dai, Meiyan; Li, Huaping; Chen, Chen; Nie, Jiali; Wang, Peihua; Wang, Dao Wen

doi:10.1161/hypertensionaha.117.09262

Cited by 32 publications

(30 citation statements)

References 47 publications

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“…In addition to local fibroblast activation, platelet-derived proteins ( 33 ), including TGF-β1 ( 19 ), contribute to the onset and progression of fibrosis. Platelet inhibition or depletion attenuates cardiac remodeling after myocardial infarction ( 48 , 49 ) or in response to pressure overload ( 18 , 33 ). We have previously demonstrated that miR-21 is abundant in platelets and miR-21 plasma levels are decreased by antiplatelet therapy ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to cardiomyocytes and CFs, high TGF-β1 levels are also found in blood platelets, where its release is controlled by Wiskott-Aldrich syndrome protein (WASp) ( 17 ). The platelet releasate is supposed to be a key driver of the inflammatory response in cardiac remodeling ( 18 ). It has been suggested that extravasated platelets are a major source of TGF-β1 in the myocardium upon cardiac injury ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of profibrotic microRNA-21 affects platelets and their releasate

Barwari¹,

Eminaga²,

Mayr³

et al. 2018

JCI Insight

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Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21–null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21–null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of profibrotic microRNA-21 affects platelets and their releasate

Barwari¹,

Eminaga²,

Mayr³

et al. 2018

JCI Insight

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“…However, the molecular mechanism by which SMYAD mediates its anti-hypertrophic effects remains unclear, and the signaling pathways that interact to drive hypertrophy are very complicated. To understand the molecular mechanisms responsible for SMYAD’s effects in HF, we investigated platelet, which has been shown to be activated in TAC-treated mice to induce cardiomyocyte hypertrophy and collagen synthesis (Wu et al, 2017a). We observed increased activation of cardiac CD41/61 and P-selectin in TAC-treated mice, as well as the reverse effect of SMYAD.…”

Section: Discussionmentioning

confidence: 99%

Si-Miao-Yong-An Decoction Protects Against Cardiac Hypertrophy and Dysfunction by Inhibiting Platelet Aggregation and Activation

Wang

Zhang

et al. 2019

Front. Pharmacol.

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Objective: The aim of this study was to determine whether Si-Miao-Yong-An decoction (SMYAD) could ameliorate pressure overload-induced heart hypertrophy and its mechanisms.Methods: C57BL/6 mice were subjected to either sham or transverse aortic constriction (TAC) surgery to induce heart hypertrophy. SMYAD (14.85 g/kg/day, ig) or captopril (16.5 mg/kg/day, ig) was administered to the mice for 4 weeks. Cardiac function was evaluated based on echocardiography. Heart hypertrophy was detected using hematoxylin and eosin or wheat germ agglutinin staining. Protein expression of CD41, CD61, and P-selectin were measured with Western blot and immunohistochemistry. The expression levels of atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain, β-thromboglobulin, and von Willebrand factor were evaluated by quantitative polymerase chain reaction.Results: Four weeks after TAC, mice developed exaggerated cardiac hypertrophy and demonstrated a strong decrease in left ventricular ejection fraction compared with sham (29.9 ± 9.3% versus 66.0 ± 9.9%; P < 0.001). Conversely, SMYAD improved cardiac dysfunction with preserved left ventricular ejection fraction (66.5 ± 17.2%; P < 0.001). Shortening fraction was increased by SMYAD, while the left ventricular internal diameter and left ventricular volume were decreased in SMYAD group. SMYAD treatment significantly attenuated cardiac hypertrophy as reflected by the inhibition of atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain mRNA expression, and by the decreasing of cardiac myocyte cross-sectional area. Furthermore, Western blot and immunohistochemistry indicated that the protein expression of platelet aggregation markers (CD41 and CD61) and platelet activation marker (P-selectin) were significantly higher in model mice compared with control. These pathological alterations in TAC-induced mice were significantly ameliorated or blocked by SMYAD administration.Conclusions: Our results suggested that SMYAD exerted its effect by inhibiting platelet aggregation and activation as revealed by CD41/CD61/P-selectin downregulation. Inhibition the activation of the platelets might contribute to the therapeutic effect of SMYAD in failing heart.

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“…11-HETE and four kinds of EETs were purchased from Cayman Chemical (Ann Arbor, Michigan, USA). For the purchasing information on some of the other conventional reagents in our lab, please refer to our previous articles [15, 20, 21].…”

Section: Methodsmentioning

confidence: 99%

PPARα ligand, AVE8134, and cyclooxygenase inhibitor therapy synergistically suppress lung cancer growth and metastasis

Wang

Dai

et al. 2019

BMC Cancer

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BackgroundLung cancer (LC) is one of the leading causes of death worldwide, which highlights the urgent need for better therapies. Peroxisome proliferator-activated nuclear receptor alpha (PPARα), known as a key nuclear transcription factor involved in glucose and lipid metabolism, has been also implicated in endothelial proliferation and angiogenesis. However, the effects and potential mechanisms of the novel PPARα ligand, AVE8134, on LC growth and progression remain unclear.MethodsA subcutaneous tumour was established in mice by injecting TC-1 lung tumour cells (~ 1 × 106 cells) into their shaved left flank. These mice were treated with three different PPARα ligands: AVE8134 (0.025% in drinking water), Wyeth-14,643 (0.025%), or Bezafibrate (0.3%). Tumour sizes and metastasis between treated and untreated mice were then compared by morphology and histology, and the metabolites of arachidonic acid (AA) were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition of either Cyp2c44 expression by genetic disruption or cyclooxygenase (COX) activity by indomethacin was used to test the mechanisms by which AVE8134 affects tumour growth.ResultsThe pharmacodynamics effects of AVE8134, Wyeth-14,643, and Bezafibrate on lipids control were similar. However, their effects on tumour suppression were different. Eicosanoid profile analysis showed that all PPARα ligands reduced the production of AA-derived epoxyeicosatrienoic acids (EETs) and increased the hydroxyl product, 11-hydroxyeicosatetraenoic acids (11-HETE). Moreover, increased 11-HETE promoted endothelial proliferation, angiogenesis, and subsequent tumour deterioration in a dose-dependent manner possibly via activating the AKT/extracellular signal-regulated kinase (ERK) pathway. The increased 11-HETE partly neutralized the benefits provided by the Cyp2c44-EETs system inhibited by PPARα ligands in tumour-bearing mice. AVE8134 treatment worsened the tumour phenotype in Cyp2c44 knockout mice, indicating that AVE8134 has contradictory effects on tumour growth. The COX inhibitor indomethacin strengthened the inhibitory actions of AVE8134 on tumour growth and metastasis by inhibiting the 11-HETE production in vivo and in vitro.ConclusionIn this study, we found that the degrees of inhibition on LC growth and metastasis by PPARα ligands depended on their bidirectional regulation on EETs and 11-HETE. Considering their safety and efficacy, the novel PPARα ligand, AVE8134, is a potentially ideal anti-angiogenesis drug for cancer treatment when jointly applied with the COX inhibitor indomethacin.

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P2y12 Receptor Promotes Pressure Overload–Induced Cardiac Remodeling via Platelet-Driven Inflammation in Mice

Cited by 32 publications

References 47 publications

Inhibition of profibrotic microRNA-21 affects platelets and their releasate

Inhibition of profibrotic microRNA-21 affects platelets and their releasate

Si-Miao-Yong-An Decoction Protects Against Cardiac Hypertrophy and Dysfunction by Inhibiting Platelet Aggregation and Activation

PPARα ligand, AVE8134, and cyclooxygenase inhibitor therapy synergistically suppress lung cancer growth and metastasis

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