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Variable Effects Of LDL Subclasses Of Cholesterol On Endothelial Nitric Oxide/Peroxynitrite Balance - The Risks And
Jiangzhou Hua1, Tadeusz Malinski1
1Nanomedical Research Laboratory, Ohio University, Athens, OH, USA.
Insights
Low-density lipoprotein (LDL) subclass B significantly damages endothelial function, increasing atherosclerosis risk. Measuring LDL subclass B concentrations, not total LDL, may improve heart attack risk assessment and enable targeted therapies.
Area of Science:
- Cardiovascular Science
- Nanomedicine
- Biochemistry
Background:
- Elevated low-density lipoprotein (LDL), or "bad cholesterol", is not a reliable indicator of coronary disease risk.
- Approximately 75% of individuals experiencing heart attacks have cholesterol levels that do not suggest high cardiovascular risk.
- LDL comprises three subclasses (A, B, and I) with varying particle sizes and densities, influencing their impact on health.
Purpose of the Study:
- To investigate the detrimental effects of LDL subclasses on endothelial cells using nanomedical systems.
- To elucidate the role of specific LDL subclasses in endothelial dysfunction and atherosclerosis development.
Main Methods:
- Nanosensors were utilized to quantify nitric oxide (NO) and peroxynitrite (ONOO-) concentrations stimulated by different LDL subclasses in human umbilical vein endothelial cells (HUVECs).
- The ratio of nitric oxide to peroxynitrite (NO/ONOO-) was employed to assess the harmful impact of LDL subclasses on endothelium.
- Native LDL (n-LDL) and oxidized LDL (ox-LDL) across subclasses A, B, and I were analyzed.
Main Results:
- The NO/ONOO- ratio, indicative of endothelial health, shifted significantly from approximately 5 in normal endothelium to 2.7±0.4 (A), 0.5±0.1 (B), and 0.9±0.1 (I).
- LDL subclass B demonstrated the most potent adverse effects, significantly increasing the adhesion of molecules and monocytes.
- A mixture of 50% subclass B and 50% subclass I LDL induced the most severe NO/ONOO- imbalance (0.45±0.04), while a specific combination of A, B, and I subclasses showed a favorable balance (5.66±0.69).
- Oxidized LDL exhibited a more pronounced detrimental effect compared to native LDL.
Conclusions:
- LDL subclass B is identified as the most atherogenic subclass, significantly impairing endothelial function and contributing to atherosclerosis.
- The study suggests that LDL subclass B concentration, relative to subclasses A and/or I, should be prioritized for diagnosing atherosclerosis and heart attack risk over total LDL levels.
- Targeting LDL subclass B with specific pharmacological therapies holds potential for significantly reducing the risk of heart attack and atherosclerosis.
Background:
Elevated levels of low density lipoprotein (LDL), "bad cholesterol", is not an accurate indicator of coronary disease. About 75% of patients with heart attacks have cholesterol levels that do not indicate a high risk for a cardiovascular event. LDL is comprised of three subclasses, with particles of different size and density. We used nanomedical systems to elucidate the noxious effects of LDL subclasses on endothelium.
Experimental:
Nanosensors were employed to measure the concentrations of nitric oxide (NO) and peroxynitrite (ONOO-) stimulated by LDL subclasses in HUVECs. N-LDL and ox-LDL (subclass A: 1.016-1.019 g/mL, subclass I: 1.024-1.029 g/mL, and subclass B: 1.034-1.053 g/mL) stimulated NO and ONOO- release. The concentrations ratio of (NO)/(ONOO-) was used to evaluate the noxious effects of the subclasses on endothelium.
Results:
In HUVECs, the (NO)/(ONOO-) ratio for normal endothelium is about 5, but shifts to 2.7±0.4, 0.5±0.1, and 0.9±0.1 for subclasses A, B, and I, respectively. Ratios below 1.0 indicate an imbalance between NO and ONOO-, affecting endothelial function. LDL of 50% B and 50% I produced the most severe imbalance (0.45±0.04), whereas LDL of 60% A, 20% B, and 20% I had the most favorable balance of 5.66±0.69. Subclass B significantly elevated the adhesion of molecules and monocytes. The noxious effect was significantly higher for ox-LDL than n-LDL.
Conclusion:
Subclass B of "bad cholesterol" is the most damaging to endothelial function and can contribute to the development of atherosclerosis. Contrary to the current national guidelines, this study suggests that it's not the total LDL, rather it is the concentration of subclass B in relation to subclasses A and/or I, that should be used for diagnosis of atherosclerosis and the risk of heart attack. By utilizing specific pharmacological therapy to address the concentration of subclass B, there is a potential to significantly reduce the risk of heart attack and atherosclerosis.
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