Raising HDL cholesterol levels may reduce the risk of myocardial ischaemia/reperfusion injury

Administration of high-density lipoprotein (HDL) or one of its constituents, sphingosine-1-phosphate (S-1-P) protected against acute myocardial ischaemia/reperfusion injury in a mouse model. Based on these findings, raising HDL cholesterol levels could prove beneficial in patients at high risk of acute myocardial ischaemia.1

The current focus in managing acute myocardial infarction is rapid reperfusion of the infarcted myocardium by revascularisation of the occluded vessel. However, endothelial injury and inflammation that follow reperfusion (referred to as ischaemia/reperfusion injury) may compromise beneficial effects. No strategies are currently available to protect against this complication.

Sphingolipids such as S-1-P are constituents of HDL, responsible for part of the vasodilatory effects of HDL.2 Acute administration of reconstituted HDL normalises endothelial dysfunction in patients with raised cholesterol, via a mechanism that is mediated by nitric oxide (NO).3

Using a mouse model of myocardial reperfusion injury (involving 30 minutes of ischaemia followed by 24-hour reperfusion), researchers showed that prior intravenous administration of human HDL or S-1-P markedly attenuated the size of the infarction (by 20% and 40%, respectively). Further study showed that HDL and S-1-P achieved this effect by inhibiting inflammation and protecting cardiomyocytes (containing S-1-P receptors) against apoptosis, a process involving a genetically programmed series of events leading to the death of a cell. Cardioprotection mediated by HDL and S-1-P was dependent on NO, as inhibition of NO synthase, responsible for production of NO, before myocardial ischaemia/reperfusion completely abolished these effects. Additionally, neither HDL nor S-1-P had any effect in mice that were deficient in the S-1-P3 receptor, which binds both S-1-P and HDL and is involved in NO production. The authors concluded that HDL and its constituent S-1-P acutely protect the heart against ischaemia/reperfusion injury via an S-1-P3-mediated and NO-dependent pathway.

In patients at risk of myocardial ischaemia, levels of HDL and HDL-associated S-1-P may influence the extent of myocardial damage after acute ischaemia. Therapeutic strategies aimed at rapidly raising HDL levels and their S-1-P content may therefore represent a novel approach to counter reperfusion injury in such settings.

References

1. Theilmeier G, Schmidt C, Herrmann J et al. High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the SIP3 lysophospholipid receptor. Circulation 2006;114:1403-9.

2. Nofer JR, van der Giet M, Tolle M et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor SIP3. J Clin Invest 2004;113:569-81.

3. Spieker LE, Sudano I, Hurlimann D et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 2002;105:1399-1402.

Commentary

In line with the hypothesis that HDL-associated S-1-P may be implicated in the molecular and cellular mechanisms underlying the anti-apoptotic action of HDL on endothelial cells, these studies in a mouse model extend the cytoprotective role of HDL associated S-1-P to cardiomyocytes in the context of post-infarct reperfusion injury subsequent to infarct-induced ischaemia. Infusion of S-1-P-enriched HDL in the acute phase of myocardial infarction may therefore represent an innovative therapy to attenuate ischaemic myocardial damage.