Lesions have fewer dead macrophages if cholesterol does not get to the ER (right).

Tabas/NAS

A high-cholesterol diet can be the fast track to a heart attack. But scientists are only now discovering that one of cholesterol's most damaging effects might stem from its ability to make blood cells self-destruct. The findings appear in a pair of recent studies directed by Ira Tabas (Columbia University, New York, NY).

Cholesterol is abundant in atherosclerotic lesions, which become most dangerous when they break apart and plug an arterial passage. Unstable lesions are associated with lots of cellular debris, mostly from dead macrophages. Tabas, along with Bo Feng and colleagues, shows in one article that macrophages die in lesions because cholesterol elicits the unfolded protein response (UPR) in the ER.

Macrophages that were unable to deal with the excess cholesterol they ingested had depleted ER calcium stores and activated the UPR, which can cause cell death. The UPR and cell death were prevented if cholesterol trafficking to the ER was blocked. Tabas speculates that cholesterol might deplete calcium stores by stiffening the ER membrane (which normally contains very little cholesterol), thus impairing integral proteins that pump in calcium and presumably disabling calcium-dependent chaperones.

The group used low doses of a drug to prevent cholesterol trafficking to the ER in cell cultures, but they also found an in vivo mutation that worked just as well—heterozygous mutations in the late endosomal protein NPC1. In a second article, Feng, Dajun Zhang, Tabas, and colleagues examined lesions in these heterozygous mice. Compared with homozygous NPC1 mice, the npc1 heterozygotes had lesions with less necrosis and fewer apoptotic macrophages.

Long-term studies are still needed to establish whether lesions in NPC1 heterozygous mice are less apt to rupture. But according to Tabas, “our results have already spawned a clinical study to determine if [NPC heterozygous humans] are protected against acute cardiovascular events.” If the results are positive, drugs to block cholesterol transport to the ER may follow. ▪

References:

Feng, B., et al. 2003. Proc. Natl. Acad. Sci. USA.. 10.1073/pnas.1732494100.

Feng, B., et al. 2003. Nat. Cell Biol. 10.1038/ncb1035.