New research explaining why only a small percentage of fatty deposits in blood vessels lead to serious heart disease holds promise for future treatments, researchers claim.
The 'vast majority' of blood vessel lesions caused by plaques - accumulations of fatty deposits such as cholesterol - are harmless but others can lead to acute blood clots, heart attacks or stroke.
'The billion dollar question is why 98 per cent cause no problem and two per cent do,' said Ira Tabas of Columbia University in Cell Metabolism.
Professor Tabas and his team believe that, by isolating the dangerous blood vessel plaques, new drugs could be created to tackle cellular distress.
Tests on mice pointed heavily to endoplasmic reticulum (ER) stress and the body's natural way of coping with stress is one answer.
The ER is a cellular component that serves two major functions as the site where new proteins are made, folded and transported, and also the central storage depot for the cell's calcium.
When insults to the cell throw those functions off kilter, cells handle the imbalance via a pathway known as the unfolded protein response (UPR). If times get really tough, that pathway simply kills off the cells that are suffering. That decision to die is commandeered by an ER stress effector known as CHOP.
'When cells die, it's okay as long as it's not en masse,' Professor Tabas explained. 'It's a wonderful path to keep the ER in check, and by killing a cell here and there because of uncorrectable ER stress, the pathway protects the whole organism. In pathologies, however, this pathway gets over exuberant.'
In the case of clogged blood vessels, known as atherosclerosis, ER stress within plaques could lead to the massive death of cells, prompting the generation of a structure called the 'necrotic core'.
These necrotic cores are known to be a defining feature of plaques that are vulnerable to rupture and blood clot formation. While earlier studies had suggested a correlation between ER stress and vulnerable plaques, the new study is the first to show a clear causal connection between the two.
Professor Tabas' group studied two separate strains of mice, each carrying a specific genetic alteration that makes them especially prone to develop atherosclerosis. The mice also lacked CHOP.
When fed a diet high in fat and cholesterol for ten weeks, one strain of these CHOP deficient mice with atherosclerosis developed smaller lesions than mice with CHOP, the researchers claim.
Most importantly, cell death and plaque necrosis dropped by about 50 per cent. The second strain of atherosclerotic mice showed essentially the same result.
'The fact that we were able to isolate one gene encoding one protein with such a profound effect on plaque necrosis was a big surprise,' Professor Tabas said.
'The results of this study, together with recent findings showing expression of CHOP in vulnerable human atherosclerotic plaques, suggest that the CHOP pathway may be a potential therapeutic target related to the formation of dangerous atheromata,' the researchers write.
'In particular, it will be interesting to determine whether so-called chemical chaperones, which have been successfully used in other animal models of UPR-associated diseases, have a beneficial effect on advanced atherosclerotic lesion progression.'