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

Abstract

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.

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

“…In ischemic cardiomyopathy, activation of HIF-1α leads to up-regulation of LRP-1 [22, 27]. These receptors, unlike LDLR, seem to be responsible for cholesterol accumulation in cardiomyocytes.…”

Probucol Protects Endothelial Progenitor Cells Against Oxidized Low-Density Lipoprotein via Suppression of Reactive Oxygen Species Formation In Vivo

“…The protein concentration in the lipoproteins was determined using the Lowry's method. Ox-LDL was produced from the native LDL immediately after dialysis using 5 μM copper sulphate, and was stopped by adding EDTA (0.25 mM, final concentration) as described [51].…”

Lipoproteins: A Source of Cardiac Lipids

“…Cardiomyocyte LOX-1 expression is increased by endothelin and norepinephrine [ 71 ] and it seems to aggravate heart failure. Activation of LOX-1 by oxidized LDL leads to increased release of reactive oxygen species [ 110 ], apoptosis [ 71 ], cardiomyocyte damage [ 111 ] and elevation of heart failure biomarkers, such as brain natriuretic peptide and monocyte chemoattractant protein-1 [ 112 ]. LOX-1 expression is induced by angiotensin-mediated hypertrophy [ 113 , 114 ] and is inhibits by curcumin and rosuvastatin, which also inhibits cardiomyocyte growth [ 113 , 114 ].…”

“…Specifi cally, LOX-1 increased in rat cardiomyocytes following ischemia-reperfusion, while administration of anti-LOX-1 antibody reduced myocardial infarction size [ 120 ] and LOX-1 genetic deletion reduced ischemia-driven collagen accumulation [ 121 ]. Therefore, LOX-1 appears to be involved in ischemic heart failure as it activates stress signaling kinases, such as JNK and ERK [ 112 ]. Accordingly, treatment of mouse cardiomyocytes with JNK or ERK inhibitors prevented ox-LDL-induced increase of BNP [ 112 ].…”

“…Therefore, LOX-1 appears to be involved in ischemic heart failure as it activates stress signaling kinases, such as JNK and ERK [ 112 ]. Accordingly, treatment of mouse cardiomyocytes with JNK or ERK inhibitors prevented ox-LDL-induced increase of BNP [ 112 ]. The benefi cial effect of LOX-1 inhibition in ischemia has been attributed to reduced myocardial oxidative stress and inhibition of pathological NF-κB, JNK and p38 MAPK signaling pathways [ 121 ].…”