Abstract 835: Left Ventricular Expression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Serves as a Biomarker of Heart Failure in the Salt-Sensitive Dahl Rat Model of Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tomohide Takaya ◽  
Tatsuya Morimoto ◽  
Yoichi Sunagawa ◽  
Hiromichi Wada ◽  
Teruhisa Kawamura ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rat Model ◽  
Systolic Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
Left Ventricular ◽  
Low Density ◽  
Mrna Levels ◽  
Oxidized Low Density Lipoprotein

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) was originally identified as an endothelial receptor for oxidized LDL, and now is recognized as a multi-ligand receptor. LOX-1 expression in cardiomyocytes can be induced by oxidative stress and various hormonal stimuli. Activation of the LOX-1 pathway in cardiomyocytes induces apoptosis in vitro and deteriorates ischemia-reperfusion injury in vivo . However the role of LOX-1 in chronic heart failure is unknown. We examined the left ventricular (LV) expression of LOX-1 in a salt-sensitive Dahl (DS) rat model of hypertension. Compared with control salt-resistant Dahl (DR) rats, a high-salt diet, started at the age of 6 weeks, induced marked hypertension and apparent concentric LV hypertrophy on echocardiography in DS rats. The LV hypertrophy was moderate at the age of 11 weeks and marked at 18 weeks. The LV systolic function was preserved at 11 weeks, and decreased at 18 weeks. Quantitative real-time PCR revealed a 4.7-fold increase in LV levels of LOX-1 mRNA in DS rats compared with DR rats at 11 weeks, and a 32-fold increase at 18 weeks. The LV LOX-1 mRNA levels were significantly correlated with the LV end-systolic dimension (R=0.640, p=0.0002), and LV posterior wall thickness (R=0.555, p=0.0022), as well as the LV/body weight ratio (R=0.647, p=0.0002), and systolic blood pressure (R=0.751, p<0.0001). LOX-1 levels were also connected with an increase in LV mRNA levels of heme oxygenase-1 (R=0.692, p<0.0001), a marker of oxidative stress. Importantly, LOX-1 levels were strongly associated with a decrease in the LV ejection fraction (R=0.774, p<0.0001) and an increase in mRNA levels of BNP (R=0.814, p<0.0001), a representative marker of LV wall stress and heart failure. Immunohistochemistry demonstrated LOX-1 expression in cardiomyocytes as well as vessel walls of both DS and DR rat hearts. However, expression in cardiomyocytes was greater in DS than in DR. These findings demonstrate that LV cardiomyocyte expression of LOX-1 is markedly increased in proportion to the extent of heart failure and possibly involved in the deterioration of systolic function in the DS rat model of hypertension.

Abstract 302: Presence of Oxidized Low-Density Lipoprotein in the Left Ventricular Blood of Subjects with Cardiovascular Diseases

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Chandrakala Aluganti Narasimhulu ◽  
Dmitry Litvinov ◽  
Danielle Jones ◽  
Chittoor Sai-Sudhakar ◽  
Michael Fristenberg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Left Ventricular ◽  
Paraoxonase 1 ◽  
Left Ventricular Ejection ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Peripheral Tissues ◽  
Significant Difference

Hypothesis: Oxidized low density lipoprotein (Ox-LDL) has properties that profoundly affect cardiovascular function. We hypothesized that Ox-LDL is likely to be formed in the left ventricular blood (LVB) when the heart is subjected to ischemic conditions and the ejection fraction (EF) is low. We speculated whether “stagnation” of LDL in the LV could result in increased formation of Ox-LDL. Objective: We studied whether there is an increased level of Ox-LDL in the LVB as opposed to peripheral blood (PB), and whether its presence correlated with the EF. Also we examined whether a higher level of Ox-LDL negatively correlated with the activity of paraoxonase 1 (PON 1). Methods: Following the Institutional Review Board (IRB) approval, 62 HF patients were enrolled in the study. All patients underwent pre-operative transthoracic echocardiographic assessment of ventricular function. Left ventricular ejection fractions were determined using the Simpsons bi-plane technique. 2ml of LVB and 5ml of PB samples were taken before coronary artery bypass surgery, or a surgery with replacement of mitral, aortic or tricuspid valve. Blood level of Ox-LDL was determined by ELISA (Mercodia), and PON 1 activity was determined by the rate of conversion of its substrate p-nitrophenyl acetate into p-nitrophenol. Results: The result showed significant increase in Ox-LDL in LVB as compared to PB (p=0.032) in HF subjects even when EF was near normal. There was no significant increase in subjects with lower EF. In contrast, Ox-LDL levels increased in the PB of subjects with lower EF and reached those of LVB. We also noticed that there was a statistically significant negative correlation between EF and Ox-LDL levels in both LVB and PB (p < 0.05). The activity of PON1, an antioxidant enzyme that protects LDL from oxidation showed decreased levels both in LV blood as well as in PB with decreased EF. It was observed that there was a statistically significant difference in PON1 levels between LV and PB of subjects having EF>60% (p = 0.03). Conclusions: In conclusion the results suggest that there might be oxidative stress associated with LVB even when the EF is not compromised. In contrast, the increase in PB Ox-LDL with poor EF might suggest that the low blood flow to peripheral tissues and end organs also might contribute to increased oxidative stress. The results also might suggest that persistent oxidative stress could have affected the clearance mechanisms of Ox-LDL.

scholarly journals Lectin-Like Oxidized Low-Density Lipoprotein 1 Receptor in a Reduced Uteroplacental Perfusion Pressure Rat Model of Preeclampsia

Hypertension ◽  
2012 ◽  
Vol 59 (5) ◽  
pp. 1014-1020 ◽  
Author(s):  
Jude S. Morton ◽  
Ali Abdalvand ◽  
Yanyan Jiang ◽  
Tatsuya Sawamura ◽  
Richard R.E. Uwiera ◽  
...  
Keyword(s):  
Rat Model ◽  
Perfusion Pressure ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure

2012 ◽  
Vol 302 (1) ◽  
pp. C165-C177 ◽  
Author(s):  
Aluganti N. Chandrakala ◽  
Devraj Sukul ◽  
Krithika Selvarajan ◽  
Chittoor Sai-Sudhakar ◽  
Benjamin Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Monocyte Chemotactic Protein ◽  
Chemotactic Protein

Brain natriuretic peptide (BNP) and monocyte chemotactic protein-1 (MCP-1) are biomarkers of heart failure (HF). The aim of the present study was to determine the role of oxidized low-density lipoprotein (Ox-LDL) in the induction of these biomarkers and the signaling pathways involved in vitro. Incubation of HL-1 cardiomyocytes and human myocytes with Ox-LDL induced the expression of BNP and MCP-1 genes, while native LDL had no effect. When peroxides associated with Ox-LDL were reduced to hydroxides, the ability to induce BNP and MCP-1 gene expression was abolished. Furthermore, exposure of HL-1 cells to ischemic conditions alone had no effect on BNP gene expression, while ischemia followed by reperfusion resulted in increased expression of BNP gene. Inhibitors of ERK and JNK inhibited the induction of BNP. Signaling array results suggested that the induction of both MAPK and NF-κB pathways is involved in the induction of BNP by Ox-LDL. These results suggest that Ox-LDL or peroxidized lipids formed in oxidatively stressed myocytes during ischemia-reperfusion injury may play a role in the induction of BNP and MCP-1.

Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1α (HIF-1α) accumulation via redox-dependent mechanisms

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4847-4849 ◽  
Author(s):  
Vladimir A. Shatrov ◽  
Vadim V. Sumbayev ◽  
Jie Zhou ◽  
Bernhard Brüne
Keyword(s):  
Reporter Gene ◽  
Low Density Lipoprotein ◽  
Hypoxia Inducible Factor ◽  
Density Lipoprotein ◽  
Luciferase Reporter ◽  
Low Density ◽  
Mrna Levels ◽  
Oxidized Low Density Lipoprotein ◽  
Human Macrophages ◽  
Hypoxia Inducible Factor 1Α

Abstract Oxidized low-density lipoprotein (oxLDL) and macrophages play a central role in atherosclerosis. Here, we obtained evidence that oxLDL induced hypoxia-inducible factor-1α (HIF-1α) protein accumulation in human macrophages (Mono-Mac-6) under normoxia. HIF-1α accumulation was attenuated by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC), the nitric oxide (NO) donor S-nitrosoglutathione (GSNO), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors such as diphenyleniodonium (DPI) or 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), thus implicating the contribution of oxLDL-generated reactive oxygen species (ROS). Whereas oxLDL did not modulate HIF-1α mRNA levels, experiments with cycloheximide pointed to a translational mechanism in oxLDL action. HIF-1–dependent luciferase reporter gene analysis underscored HIF-1 transactivation. Our results indicate that oxLDL induced HIF-1α accumulation and HIF-1–dependent reporter gene activation in human macrophages via a redox-mediated pathway. This finding may suggest a role of HIF-1 in atherosclerosis and oxLDL-induced pathogenesis.

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