Overexpression of LOXIN Protects Endothelial Progenitor Cells From Apoptosis Induced by Oxidized Low Density Lipoprotein

Veas, Carlos; Jara, Casandra; Willis, Naomi D.; Pérez-Contreras, Karen; Gutiérrez, Nicolás Antonio Sáez; Toledo, Jorge R.; Fernández, P; Radojkovic, Claudia; Zúñiga, Felipe; Escudero, Carlos; Aguayo, Claudio

doi:10.1097/fjc.0000000000000358

Cited by 16 publications

(22 citation statements)

References 69 publications

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“…In the current study, various doses of ox‐LDL exposure were applied to assess the dose‐dependent effects on the A7r5 rat vascular smooth muscle cell line. While doses up to 50 μg/mL effectively induced cell proliferation, higher doses (100 μg/mL) induced cell death, which is consistent with other studies such as Veas et al (). As a result, 50 μg/mL ox‐LDL was selected for subsequent studies.…”

Section: Discussionsupporting

confidence: 91%

The anti‐proliferative effects of oleanolic acid on A7r5 cells—Role of UCP2 and downstream FGF‐2/p53/TSP‐1

Han

Jiang

Wang

et al. 2017

Cell Biology International

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Vascular smooth muscle cell (VSMC) proliferation is a major contributor to atherosclerosis. This study investigated the inhibitory effects of oleanolic acid (OA) against oxidized low-density lipoprotein (ox-LDL)-induced VSMC proliferation in A7r5 cells and explored underlying molecular mechanism. The cell proliferation was quantified with cell counting kit-8 (CCK-8), in which ox-LDL significantly increased A7r5 cells proliferation, while OA pretreatment effectively alleviated such changes without inducing overt cytotoxicity, as indicated by lactate dehydrogenase (LDH) assay. Quantitative real-time RT-PCR (qRT-PCR) and Western blotting revealed increased UCP2 and FGF-2 expression levels as well as decreased p53 and TSP-1 expression levels in A7r5 cells following ox-LDL exposure, while OA pretreatment reversed such changes. Furthermore, inhibiting UCP2 with genipin remarkably reversed the changes in the expression levels of FGF-2, p53, and TSP-1 induced by ox-LDL exposure; silencing FGF-2 with siRNA did not significantly change the expression levels of UCP2 but effectively reversed the changes in the expression levels of p53 and TSP-1, and activation of p53 with PRIMA-1 only significantly affected the changes in the expression levels of TSP-1, but not in UCP2 or FGF-2, suggesting a UCP-2/FGF-2/p53/TSP-1 signaling in A7r5 cells response to ox-LDL exposure. Additionally, co-treatment of OA and genipin exhibited similar effects to the expression levels of UCP2, FGF-2, p53, and TSP-1 as OA or genipin solo treatment in ox-LDL-exposed A7r5 cells, suggesting the involvement of UCP-2/FGF-2/p53/TSP-1 in the mechanism of OA. In conclusion, OA inhibits ox-LDL-induced VSMC proliferation in A7r5 cells, the mechanism involves the changes in UCP-2/FGF-2/p53/TSP-1.

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Section: Discussionsupporting

confidence: 91%

The anti‐proliferative effects of oleanolic acid on A7r5 cells—Role of UCP2 and downstream FGF‐2/p53/TSP‐1

Han

Jiang

Wang

et al. 2017

Cell Biology International

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“…Furthermore, reduced number of circulating hEPCs has been found in patients with hypercholesterolemia, which correlates with the fact that increased plasma cholesterol levels have been linked with endothelial damage. In the same study, the number of hEPCs was negatively correlated with total cholesterol and low-density lipoprotein (LDL) cholesterol level [78]. On the other hand, it has been also observed that the number of circulating hEPCs increases significantly after exercise [79] and in response to statins [80], antidiabetic (Pioglitazone, Sitagliptin) [81], and antihypertensive drugs (Ramipril and Enalapril) [82,83].…”

Section: Cardiovascular Risk Factors and Hepc Functionmentioning

confidence: 85%

Vascular Regeneration by Endothelial Progenitor Cells in Health and Diseases

Nova‐Lamperti¹,

Zúñiga²,

Ormazábal³

et al. 2016

Microcirculation Revisited - From Molecules to Clinical Practice

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Human endothelial progenitor cells (hEPCs) are adult stem cells, located in the bone marrow and peripheral blood. These cells can be differentiated into mature endothelial cells, which are involved in processes of angiogenesis and vessel regeneration. Different phenotypes and subtypes of endothelial progenitor cells (EPCs), such as early and late EPCs, have been described according to their functionality. Thus, it has been shown that early EPCs release cytokines that promote tissue regeneration and neovasculogenesis, whereas late EPC and endothelial colony forming cells (ECFCs) contribute to the formation of blood vessels and stimulate tube formation. It has been demonstrated that the number of circulating hEPC is decreased in individuals with hypercholesterolemia, hypertension, and/or diabetes. In addition, the number and the migratory activity of these cells are inversely correlated with risk factors such as hypertension, hypercholesterolemia, diabetes, and metabolic syndrome. On the other hand, the number of circulating hEPC is increased in hypoxia or acute myocardial infarction (AMI). hEPCs have been used for cell-based therapies due to their capacity to contribute in the reendothelialization of injured blood vessels and neovascularization in ischemic tissues. This chapter provides an overview of the key role of hEPC in promoting angiogenesis and their potential use for cell therapy.

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“…The LOXIN/LOX-1 heterodimers result in the disruption of the functional properties of LOX-1 and increase the resistance of cells to ox-LDL-induced apoptosis [142]. A recent study performed in human endothelial progenitor cells (hEPC), demonstrated that overexpression of LOXIN protected hEPC from ox-LDL-induced apoptosis and that transduced LOXIN localized to the plasma membrane and blocked ox-LDL uptake mediated by LOX-1 [143]. Furthermore, LOX-1 is highly expressed in vascularized tissues such as placenta [128], which prompted its potentially crucial role in placental function during the earliest stages of pregnancy [144].…”

Section: Olr1 Alternative Splicing: One Gene—three Proteinsmentioning

confidence: 99%

“…For instance, homozygous “Risk” haplotype subjects show a higher OLR1 / Loxin ratio compared with those homozygous for the “non-Risk” haplotype (Figure 7B) [156]. The greater expression of Loxin transcript in subjects carrying the “non-Risk” haplotype (Figure 7C) suggests a negative link between levels of Loxin and the incidence of MI in humans, portraying Loxin as a “protective” splice isoform in cardiovascular pathologies [142,143,156]. …”

Section: Olr1 Splicing Regulationmentioning

confidence: 99%

LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies

Rizzacasa

Morini

Pucci

et al. 2017

IJMS

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Alternative splicing (AS) is a process in which precursor messenger RNA (pre-mRNA) splicing sites are differentially selected to diversify the protein isoform population. Changes in AS patterns have an essential role in normal development, differentiation and response to physiological stimuli. It is documented that AS can generate both “risk” and “protective” splice variants that can contribute to the pathogenesis of several diseases including atherosclerosis. The main endothelial receptor for oxidized low-density lipoprotein (ox-LDLs) is LOX-1 receptor protein encoded by the OLR1 gene. When OLR1 undergoes AS events, it generates three variants: OLR1, OLR1D4 and LOXIN. The latter lacks exon 5 and two-thirds of the functional domain. Literature data demonstrate a protective role of LOXIN in pathologies correlated with LOX-1 overexpression such as atherosclerosis and tumors. In this review, we summarize recent developments in understanding of OLR1 AS while also highlighting data warranting further investigation of this process as a novel therapeutic target.

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Overexpression of LOXIN Protects Endothelial Progenitor Cells From Apoptosis Induced by Oxidized Low Density Lipoprotein

Cited by 16 publications

References 69 publications

The anti‐proliferative effects of oleanolic acid on A7r5 cells—Role of UCP2 and downstream FGF‐2/p53/TSP‐1

The anti‐proliferative effects of oleanolic acid on A7r5 cells—Role of UCP2 and downstream FGF‐2/p53/TSP‐1

Vascular Regeneration by Endothelial Progenitor Cells in Health and Diseases

LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies

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