The new role of LOX-1 in hypertension induced neuronal apoptosis

https://doi.org/10.1016/j.bbrc.2012.07.143Get rights and content

Abstract

Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) was originally identified as a receptor for oxLDL predominantly expressed in endothelial cells. Recently up-regulation of LOX-1 has been implicated in oxidative stress and cell apoptosis in many cell types. However, LOX-1 expression in neurons or regulation of neuronal apoptosis by LOX-1 has not been reported. To investigate the possible roles of LOX-1 in hypertension induced brain damage, we examined the distribution of LOX-1 in cortex and hippocampus and compared its expression in 32-week-old SHR and WKY rats. Immunofluorescence revealed that LOX-1 positive cells were located principally at the cortex involved in sensory information processing and were mainly expressed in neurons. We also found up-regulated mRNA expression of LOX-1, Bax and caspase-3 and down-regulated mRNA expression of Bcl-2 in SHR group. Compared with WKY group, SHR group showed increased LOX-1 positive cells and TUNEL positive cells. Furthermore, double-labeling method indicated that LOX-1 expression was colocalized with TUNEL positive cells, which means that LOX-1 expression was involved in hypertension related cell apoptosis. These findings indicated that LOX-1 expression was up-regulated in the cortex of SHR and its expression has implication in neuronal apoptosis. Elevated Bax/Bcl-2 ratio may be involved under this event.

Highlights

ā€¢ LOX-1 was expressed in neurons of cortex involved in sensory information processing. ā€¢ SHR group showed more LOX-1-positive neurons compared with age-matched WKY rats. ā€¢ LOX-1 was colocalized with apoptotic cells and was involved in neuronal apoptosis. ā€¢ Elevated Bax/Bcl-2 expression ratio may be under LOX-1 related neuronal apoptosis.

Introduction

LOX-1 is a type II membrane protein receptor for oxLDL. It has diverse roles in the host-defense system and inflammatory responses, and is involved in the pathogenesis of various diseases such as hypertension, atherosclerosis and cardiovascular diseases [1]. Recent studies showed that LOX-1 is a multiple ligand receptor induced by reactive oxygen species (ROS) and oxidative stress, and its expression can further exacerbate oxidative stress [2], thus plays an important role in oxidative stress induced cell injury [3]. It has been demonstrated that LOX-1 expressed in endothelial cells [4], smooth muscle cells [5] and monocytes/macrophages [6] are all involved in cell apoptosis. Microglia is termed as ā€œmacrophages in the central nervous system (CNS)ā€ and it has been suggested that LOX-1 may be expressed in microglia other than vascular endothelial cells in stroke [7].

Spontaneously hypertensive rats (SHR), which are normotensive at birth and develop sustained hypertension between 3 and 6Ā months of age, are the most extensively investigated model for evaluating hypertensive brain damage and its treatment [8]. The time-dependent rise of arterial blood pressure (BP), occurrence of brain atrophy and glial reaction, and loss of nerve cells are shared to some extent with what occurs in human hypertensive brain [9]. SHR, therefore, can represent a reasonable model of hypertension related brain damage. Oxidative stress is believed to play an important role in the development of hypertension and hypertension related organ damage [10]. Increased production of superoxide anion and hydrogen peroxide has been demonstrated in experimental hypertensive models [11] and human hypertension [12] based on increased levels of biomarkers of lipid peroxidation and oxidative stress.

However, there has been no exact evidence about LOX-1 expression in neurons or regulation of neuronal apoptosis by LOX-1 in SHR rats. This study was designed to explore the expression and distribution of LOX-1 in SHR and age-matched WKY rats and evaluate its role on hypertension induced neuronal apoptosis and its possible molecular mechanisms.

Section snippets

Animals

Thirty-two-week-old male SHR (nĀ =Ā 8) and WKY rats (nĀ =Ā 8) were provided by Shanghai Slac Laboratory Animal Center. All procedures were conducted according to guidelines established by the Institutional Animal Care and Use Committee and The National Institutes of Health. The rats were housed under humidity-, temperature-, and light cycle-controlled conditions, with free access to food and water. BP values were measured by an indirect tail-cuff method. Before killing, rats were anesthetized with

SHR group showed higher systolic blood pressure (SBP)

We measured the SBP level in two groups. SBP values were 103.5Ā Ā±Ā 3.6Ā mm Hg in WKY group and 184.4Ā Ā±Ā 8.1Ā mm Hg in SHR group (pĀ <Ā 0.01). The results indicated that SHR group has significantly higher SBP than age-matched WKY group.

Distribution of LOX-1 expression in SHR and WKY rats

To verify whether LOX-1 protein was expressed in CNS, we performed immunofluorescence with anti-LOX-1 antibody. Since LOX-1 was a membrane glycoprotein with a C-type lectin-like extracellular domain and a short cytoplasmic tail [4], it was mainly located in the membrane of

Discussion

In this research, we found that LOX-1 expression was increased in SHR group and was mainly distributed in the cortex involved in sensory information processing. Instead of microglia, LOX-1 was expressed in neuron and its expression was highly colocalized with the apoptotic cells. Elevated Bax/Bcl-2 expression ratio may be involved under this event. To our knowledge, this is the first evidence to clearly show LOX-1 expression in neurons and verify the relationship between LOX-1 and neuronal

Acknowledgments

We are grateful to Professor Yi Zhu for his excellent technical assistance. This work was supported in part by the National Natural Science Foundation of China (NSFC) under the Grant Nos. 81070219 and 30900617 and finished in Institute of Neurobiology, School of Medicine, Xiā€™an Jiaotong University.

References (33)

  • K. Oka et al.

    Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells

    Proc. Nat. Acad. Sci. U.S.A.

    (1998)
  • D. Li et al.

    Intracellular signaling of LOX-1 in endothelial cell apoptosis

    Circ. Res.

    (2009)
  • H. Kataoka et al.

    Oxidized LDL modulates Bax/Bcl-2 through the lectinlike ox-LDL receptor-1 in vascular smooth muscle cells

    Arterioscler. Thromb. Vasc. Biol.

    (2001)
  • S.J. Hardwick et al.

    Apoptosis in human monocyte-macrophages exposed to oxidized low density lipoprotein

    J. Pathol.

    (1996)
  • H.D. Khanna et al.

    Oxidative stress in hypertension: association with antihypertensive treatment

    Indian J. Physiol. Pharmacol.

    (2008)
  • T. Kushiro et al.

    Oxidative stress in the Dahl salt-sensitive hypertensive rat

    Clin. Exp. Hypertens.

    (2005)
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