The Inhibition of Oxidised Low-Density Lipoprotein-Induced Apoptosis of Macrophages by Recombinant Human Brain Natriuretic Peptide and the Underlying Mechanism

Abstract

Objective: Macrophage apoptosis plays a key role in atherosclerotic plaque rupture. This study investigated the effects of recombinant human brain natriuretic peptide (BNP) on oxidised low-density lipoprotein (ox-LDL)-induced macrophage apoptosis and explored the underlying mechanism. Methods: A model of ox-LDL-induced macrophage injury was established to evaluate the role of BNP. Flow cytometry was employed to detect apoptosis and changes in mitochondrial membrane potential (ΔΨm), and confocal microscopy was used to determine cellular reactive oxygen species (ROS) levels. Additionally, reverse transcription-polymerase chain reaction and colourimetry were used to detect the mRNA expression and activity, respectively, of superoxide dismutase (SOD) and malondialdehyde (MDA). Results: Ox-LDL induced macrophage apoptosis in a concentration-dependent manner, and maximum apoptosis occurred at 100 μg/ml ox-LDL (45.62 ± 2.76 vs. 6.84 ± 1.94%; p < 0.05). Conversely, BNP suppressed macrophage apoptosis, with a maximal effect at 10^-9 mol/l (18.56 ± 1.79%; p < 0.05). Compared with the control group, intracellular ROS levels increased, ΔΨm decreased, SOD mRNA expression and activity decreased and MDA mRNA expression and content increased in the 100-μg/ml ox-LDL group (527.30 ± 36.20 vs. 100.00 ± 0.00%, 3.01 ± 0.52 vs. 9.67 ± 0.51%, 0.53 ± 0.18 vs. 1.00 ± 0.00, 256.6 ± 8.20 vs. 355.8 ± 9.58 U/ml, 1.59 ± 0.23 vs. 1.00 ± 0.00 and 29.4 ± 1.68 vs. 5.94 ± 0.51 nmol/ml; p < 0.05); these effects were significantly counteracted by 10^-9 mol/l BNP (237.30 ± 30.62%, 6.55 ± 1.57%, 0.90 ± 0.07, 310.4 ± 2.97 U/ml, 1.14 ± 0.10, 20.54 ± 1.55 nmol/ml; p < 0.05). Conclusion: BNP attenuates ox-LDL-induced macrophage apoptosis by suppressing oxidative stress and preventing ΔΨm loss.

B-Type Natriuretic Peptide as a Therapeutic Strategy: Opportunities and Pitfalls

“…The work of Chang et al [2 ]in a recent issue of Cardiology adds to our knowledge concerning the beneficial effects of BNP in cardiovascular biology. The authors demonstrate that synthetic BNP reduces oxidative (ox-)LDL-induced macrophage apoptosis in vitro, even though no mechanistic explanation of the antiapoptotic effects of BNP is provided.…”

“…What does the story of nesiritide have to do with the work of Chang et al [2]? First, we should appreciate that BNP has a wide range of effects on the cardiovascular system including blood pressure reduction which is generally considered beneficial.…”

“…In a vulnerable, hypotensive patient with poorly perfused kidneys, however, it can have serious adverse consequences. Chang et al [2] utilized a cellular system for their experiments and obviously did not have the opportunity to test the effects of synthetic BNP in individuals with atherosclerotic coronary artery disease who may be at risk of adverse events due to blood pressure reduction.…”

“…It is expected that ARNIs will soon also be tested in more populations. Could the data in Chang et al [2] also be of relevance for ARNI use in acute coronary syndromes? Again, clearly, there is a need for some words of caution.…”

“…Glycosylated proBNP 1-108 also seems to represent the major form by means of which BNP immunoreactivity is released from cardiomyocytes, both in disease states and in healthy subjects. Thus, in addition to influencing the diagnostic and prognostic accuracy of the commercially available NT-proBNP assay (ProBNP assay, Roche Diagnostics, Penzberg, Germany) [6], glycosylation of proBNP 1-108 could have implications for the clinical relevance of the results by Chang et al [2 ]as limited endogenous BNP 1-32 may actually be available in healthy subjects and in patients with cardiovascular disease. Moreover, and also important for the clinical relevance of their study, the proportion of intact BNP 1-32 in patients appears to be very low because BNP 1-32 molecules are truncated from the C-terminal end [reviewed in [5]].…”