PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis

He, Chaoyong; Medley, Shayna C.; Hu, Tai‐Shan; Hinsdale, Myron E.; Lupu, Florea; Virmani, Renu; Olson, Lorin E.

doi:10.1038/ncomms8770

Cited by 114 publications

(94 citation statements)

References 66 publications

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“…PDGF-D is a relatively novel member of PDGFs, which signal via Pdgfrb. 29,30 It stimulates VSMC migration and proliferation, monocytes/macrophage recruitment, and increased secretion of MMPs in various cell types. 46,47 Although we did not assess the involvement of VSMCs specifically in this study, we did observe enhanced macrophage and T-cell infiltration and MMP expression at the site of aortic lesion.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) IIeinduced abdominal aortic aneurysm (AAA). Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À /Cyp1b1 À/À mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe À/À /Cyp1b1 þ/þ mice was coadministered the CYP1B1 inhibitor 2,3 0 ,4,5 0 -tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe À/À /Cyp1b1 þ/þ mice; mice treated with TMS or Apoe À/À /Cyp1b1 À/À mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased plateletderived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang IIeinduced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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“…Hypercholesterolemia remains one of the most important risk factors for cardiovascular morbidity and mortality [1][2][3][4]. High plasma cholesterol levels trigger a cascade of events, including inflammation [5], oxidative stress [6] and cell damage [7,8], particularly in the cardiovascular system [3]. Additionally, we have previously shown that hypercholesterolemia increases oxidative stress in different cell types [6,7,9,10], including bone marrow mononuclear cells [8].…”

Section: Introductionmentioning

confidence: 99%

Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells

et al. 2016

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BackgroundThe pharmacological inhibitor of phosphodiesterase 5 (PDE5), sildenafil, is a promising candidate for antioxidant therapy that can result in cardiovascular protection. In addition to its known effects on the cardiovascular system, hypercholesterolemia leads to increased oxidative stress and DNA damage in the bone marrow, which is a non-classical target organ of atherosclerosis. In the present study, we evaluate oxidative stress and assess the effect of genomic instability on cell cycle kinetics in atherosclerotic animals and determine if sildenafil reverses these detrimental effects in bone marrow cells.MethodsExperiments were performed in male wild-type (WT) and apolipoprotein E knockout mice (apoE−/−) (9 weeks of age). apoE−/− mice were randomly distributed into the following 2 groups: sildenafil-treated (40 mg/kg/day for 3 weeks, n = 8) and vehicle-treated (n = 8), by oral gavage. After treatment, bone marrow cells were isolated to assess the production of superoxide anions and hydrogen peroxide, determine cell cycle kinetics and evaluate the presence of micronucleated cells.ResultsSildenafil treatment reduced the cytoplasmic levels of superoxide anion (~95 % decrease, p < 0.05) and decreased hydrogen peroxide (~30 % decrease, p < 0.05). Moreover, we observed protective effects on the DNA of bone marrow cells, including normal cell cycling, decreased DNA fragmentation and a diminished frequency of micronucleated cells.ConclusionOur data reveal that the excessive production of ROS in atherosclerotic mice overcome the DNA repair pathways in bone marrow cells. The novelty of the present study is that the administration of sildenafil reduced ROS to baseline levels and, consequently, reverted the DNA damage and its outcomes in bone marrow cells.

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“…Previous studies found that YY1 participate in the transport of lipoprotein through SREBP-1a (Ericsson et al, 1999;Gauthier et al, 1999). Recently, He et al (2015) showed that STAT1 deletion alleviated inflammation of the arterial wall and decreased plaque burden through PDGFRb pathway. Laguna-Fern andez et al (2015) found that the upregulation of JAK-STAT pathway induced endothelial transcriptomic changes after ox-LDL treatment.…”

Section: Discussionmentioning

confidence: 99%

ox‐LDL increases microRNA‐29a transcription through upregulating YY1 and STAT1 in macrophages

Jian

Dai

Yao

et al. 2017

Cell Biology International

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Macrophages and oxidized low-density lipoprotein (ox-LDL) have been verified playing vital roles in the pathogenesis of atherosclerosis (AS). Previous studies demonstrated that microRNA-29a (miR-29a) was upregulated in many atherogenic process and cells, thus acting as an important participant in AS. But the detailed regulation mechanism of miR-29a in AS has not been fully understood. In our study, we demonstrated a positive feedback loop of ox-LDL-SRA-miR-29a. Furthermore, we found that YY1 and STAT1 were upregulated in ox-LDL-stimulating macrophages followed by translocation in the nucleus and binding to the transcriptional promoter region of miR-29a, thus leading to the increase of miR-29a expression. In addition, we demonstrated that JAK1/2 signaling was involved in miR-29a upregulation. Finally, we found that miR-29a played important roles in the secretion of proinflammation factors and lipid uptake in macrophages. We uncovered the molecular mechanism and provide novel insights into the function and regulatory network of miR-29a expression regulated by ox-LDL in macrophages.

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PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis

Cited by 114 publications

References 66 publications

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells

ox‐LDL increases microRNA‐29a transcription through upregulating YY1 and STAT1 in macrophages

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