Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome.

Gomaraschi M, Ossoli A, Favari E et al.
Cardiovasc Res. 2013 Jun 28. [Epub ahead of print]

Background

HDL transports cholesterol from peripheral cells, to the liver for excretion via bile and faeces. This reverse cholesterol transport (RCT) prevents arterial cholesterol accumulation [1]. HDL also has a function in the maintenance of vascular endothelium function, by influencing vascular tone, inflammation and endothelial cell homeostasis and integrity [2]. In cultured endothelial cells, HDL increases the abundance of endothelial NO synthase (eNOS) [3-5] and promotes eNOS activation, through multiple parallel pathways.
Recently it has been shown that HDL from patients with acute coronary syndrome (ACS) is unable to stimulate endothelial NO production [6]. Anti-oxidative capacity is also impaired [7], although cell cholesterol efflux is still promoted [6].
The inflammatory response in ACS is characterised by increased secretion of specific proteins by the liver. During this acute-phase response (APR), HDL is dramatically modified both in structure and in composition [8,9]. This could affect its atheroprotective capacity.
45 ACS patients were studied with ST-elevation myocardial infarction (STEMI) who developed an APR of different intensity despite comparable STEMI severity [10]. HDL of these patients was characterised to assess how APR influences the atheroprotective function of HDL during ACS. Patients were stratified in quartiles based on delta CRP (value at admission subtracted from the peak value achieved between admission and discharge (APR peak).

Main results

• HDL cholesterol, apoA-I and apoA-II levels correlated significantly and negatively with delta CRP, while LpA-I:A-II concentrations correlated positively with delta CRP.
• Inflammation had a large impact on HDL structure: a shift towards large HDL particles was observed.
• A significant inverse correlation between delta CRP and the capacity of patient HDL to activate eNOS was seen. HDL ability to stimulate NO production was also different among patient quartiles. HDL of patients in the first two quartiles showed a normal ability to activate eNOS and to promote NO production, while HDL of patients in the 3^rd and 4^th quartiles of delta CRP had significantly reduced capacities to activate eNOS and promote NO production.
• The capacity to promote cell cholesterol efflux was similar for all tested sera from all patient quartiles. However, a significant positive correlation was seen between delta CRP and delta ABCG1-mediated cholesterol efflux, consistent with the shift towards larger HDL.

Conclusion

This study demonstrates that HDL from ACS patients who develop an important inflammatory response during STEMI has an impaired capacity to stimulate eNOS and undergoes structural remodelling. Thus, only a subset of patients undergoing STEMI have circulating HDL defective in stimulating endothelial eNOS and NO production. When APR is low, HDL structure and function is preserved during STEMI. Cell cholesterol efflux through different pathways was maintained in ACS patients, irrespective of whether an inflammatory response was seen.

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