LOX-1 Plays an Important Role in Ischemia-Induced Angiogenesis of Limbs

Shiraki, Takeru; Aoyama, Takuma; Yokoyama, Chiharu; Hayakawa, Yuka; Tanaka, Toshiki; Nishigaki, Kazuhiko; Sawamura, Tatsuya; Minatoguchi, Shinya

doi:10.1371/journal.pone.0114542

Cited by 12 publications

(10 citation statements)

References 51 publications

(53 reference statements)

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“…LOX-1, an oxLDL receptor, was also reported to mediate oxLDL-induced p38 phosphorylation. In agreement with recent studies [27,28], flow-cytometric analysis showed that LOX-1 was expressed in EPCs (fig. 4a).…”

Section: Resultssupporting

confidence: 93%

Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells

Tie

Yan²,

Messina³

et al. 2015

J Vasc Res

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Oxidized low-density lipoprotein (oxLDL) is an important risk factor in the development of atherosclerosis. oxLDL has been shown to decrease endothelial progenitor cell (EPC) number by inducing apoptosis. p38 mitogen-activated protein kinase (MAPK) was shown to be activated by oxLDL and participated in the regulation of EPC number and function. However, the role of p38 remains unknown. Here, we show that oxLDL-induced p38 phosphorylation in EPCs is time and dose dependent. Treatment with antioxidant N-acetyl cysteine restored oxLDL-induced p38 phosphorylation to basal levels. LOX-1-blocking antibody also significantly decreased oxLDL-induced p38 phosphorylation. Interestingly, TUNEL staining showed that pretreatment with the p38 inhibitor SB203580 further increased oxLDL-induced apoptosis in EPCs. In accordance with these findings, pretreatment with SB203580 further attenuated Akt phosphorylation in EPCs challenged with oxLDL, indicating an interaction between Akt and p38 MAPK pathways. In agreement, inhibition of p38 MAPK further attenuated Akt phosphorylation and increased apoptosis in EPCs isolated from hypercholesterolemic ApoE-/- mice. In conclusion, p38 MAPK serves as an anti-apoptotic pathway by supporting Akt activity when EPCs are challenged with oxLDL.

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Section: Resultssupporting

confidence: 93%

Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells

Tie

Yan²,

Messina³

et al. 2015

J Vasc Res

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“…DOX increases ROS production which has been implicated in the associated cardiotoxicity and ROS sources include the mitochondrial electron transport chain, xanthine oxidase, dysfunctional NOS and NADPH oxidase [ 35 ]. Activated LOX-1 enhances ROS production via Nox2 NADPH oxidase [ 20 , 36 ]. Therefore, we measured ROS generation in the hearts after DOX or vehicle treatment by using the SOD Assay Kit.…”

Section: Resultsmentioning

confidence: 99%

“…LOX-1 KO mice with a C57/BL6J background were produced as described previously [ 20 ] and LOX-1 KO mice and control wild-type (WT) C57/BL6J strain mice were a kind gift from Dr. Tatsuya Sawamura (National Cerebral and Cardiovascular Center, Suita, Japan/ Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan). Male LOX-1 KO mice and WT mice were used at the age of 12 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Expressions of LOX-1, VCAM-1 (abcam), GATA-4, MHC and troponin-I (Santa Cruz Biotechnology), total or phosphorylated p65 subunit of NF-κB, MAPKs, Akt (Cell Signaling), were assessed by Western blotting [ 20 ]. The blots were visualized using chemiluminescence (LumiGLO, Cell Signaling), and the signals of the bands were quantified with a Calibrated Imaging Densitometer (LAS-3000IR; FUJIFILM).…”

Section: Methodsmentioning

confidence: 99%

“…Soluble LOX-1 cleaved within the cytoplasmic domain of the cell membrane was found to be significantly elevated in patients with acute coronary syndrome and stable coronary artery disease [ 17 – 19 ]. Moreover, we have recently found LOX-1 plays an important role in ischemia-induced angiogenesis and reported this novel physiological function of LOX-1 [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin

Yokoyama¹,

Aoyama²,

Ido³

et al. 2016

PLoS ONE

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Oxidative stress is one of the major factors in doxorubicin (DOX)-induced cardiomyopathy. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) plays an important role to regulate cardiac remodeling and oxidative stress after ischemia-reperfusion. Therefore, we examined whether or not LOX-1 contributes to the pathogenesis of DOX-induced cardiomyopathy. Cardiomyopathy was induced by a single intraperitoneal injection of DOX into wild-type (WT) mice and LOX-1 knockout (KO) mice. Echocardiography and catheter-based hemodynamic assessment apparently revealed preserved left ventricular (LV) fractional shortening (FS) and cavity size of LOX-1 KO mice compared with those of WT mice after DOX administration. Less production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) was observed in LOX-1 KO mice than WT mice after DOX administration. Western blotting analysis also showed lower activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in LOX-1 KO mice treated with DOX than WT mice treated with DOX. In fact, NF-κB-dependent gene expressions of LOX-1 and vascular cell adhesion molecule-1 (VCAM-1) were suppressed in LOX-1 KO mice treated with DOX compared with WT mice treated with DOX. Therefore, histological analyses showed attenuation of leukocyte infiltration and cardiac fibrosis in LOX-1 KO mice compared with WT mice. Meanwhile, extracellular signal-regulated kinase MAPK (ERK) inactivation and decreased expression of sarcomeric proteins and related transcription factor GATA-4 in WT mice treated with DOX administration were not seen in LOX-1 KO mice treated with DOX administration and WT and LOX-1 KO mice treated with vehicle. Decreased expression of sarcometric proteins resulted in smaller diameters of cardiomyocytes in WT mice than in LOX-1 KO mice after DOX treatment. The expression of LOX-1 in cardiomyocytes was much more abundant than that in endothelial cells, fibroblasts and inflammatory cells. Endothelial cells, fibroblasts and inflammatory cells treated with DOX showed no elevated LOX-1 expression compared with those treated with vehicle. However, cardiomyocytes treated with DOX showed much more expression of LOX-1 than those treated with vehicle. Immunohistochemistry study also showed that LOX-1 expression was strongly elevated in cardiomyocytes in the heart tissue of mice treated with DOX in vivo. We conclude that LOX-1 in cardiomyocytes plays the most important roles in the pathology of DOX-induced cardiomyopathy. LOX-1 deletion altered the LOX-1-related signaling pathway, which led to improvements in cardiac function, myocardial inflammation, fibrosis and degenerative changes after DOX treatment.

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Potential Contributions of Intimal and Plaque Hypoxia to Atherosclerosis

Fong

2015

Curr Atheroscler Rep

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Injury of arterial endothelium by abnormal shear stress and other insults induces migration and proliferation of vascular smooth muscle cells (VSMCs), which in turn leads to intimal thickening, hypoxia, and vasa vasorum angiogenesis. The resultant new blood vessels extend from the tunica media into the outer intima, allowing blood-borne oxidized low-density lipoprotein (oxLDL) particles to accumulate in outer intimal tissues by extravasation through local capillaries. In response to oxLDL accumulation, monocytes infiltrate into arterial wall tissues, where they differentiate into macrophages and subsequently evolve into foam cells by uptaking large quantities of oxLDL particles, the latter process being stimulated by hypoxia. Increased oxygen demand due to expanding macrophage and foam cell populations contributes to persistent hypoxia in plaque lesions, whereas hypoxia further promotes plaque growth by stimulating angiogenesis, monocyte infiltration, and oxLDL uptake into macrophages. Molecularly, the accumulation of hypoxia-inducible factor (HIF)-1α and the expression of its target genes mediate many of the hypoxia-induced processes during plaque initiation and growth. It is hoped that further understanding of the underlying mechanisms may lead to novel therapies for effective intervention of atherosclerosis.

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LOX-1 Plays an Important Role in Ischemia-Induced Angiogenesis of Limbs

Cited by 12 publications

References 51 publications

Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells

Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells

Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin

Potential Contributions of Intimal and Plaque Hypoxia to Atherosclerosis

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