Scientists have shed new light on RCAN1 and suggest that inhibiting this protein may provide successful treatments for atherosclerosis.
Atherosclerosis is a disease which involves narrowing of the arteries due to a build-up of cholesterol and other fatty substances. As a major cause of stroke, heart attack and other cardiovascular diseases, atherosclerosis is a big problem both in the UK and worldwide.
The problem is that when cholesterol levels get too high – especially Low Density Lipoprotein (LDL) cholesterol – it starts to form a plaque on the inside of the artery. If this plaque gets big enough the blood vessel can narrow which reduces blood flow to the organs and tissues in the body meaning they don’t get enough oxygen.
If untreated, calcium can come along and cause even more problems by hardening the plaque itself; and a hardened plaque is an unhappy plaque! It gets all agitated and unstable which means it’s at greater risk of rupturing the blood vessel and breaking off. If this happens the plaque can travel in the blood and reach the brain to cause a stroke, or it can damage the blood vessels in the heart and cause a heart attack.
As if that wasn’t enough, if the plaque sits there for a long time it can induce the migration of more fats and LDLs to the site, increasing the size of the plaque.
However, our bodies have a plan! The accumulation of this ‘bad cholesterol’ sets in motion a series of events which attracts a nifty set of white blood cells called macrophages to the site of the plaque. These macrophages can then begin to eat away (phagocytose) the plaque.
Think of it like this: your arteries are roads and LDLs are cars. In atherosclerosis the car breaks down and has to pull over to the side of the road (cholesterol build up). While it’s stranded, more cars (LDLs) stop to help and in doing so block a bit of the road (forming a plaque). After a while, the breakdown service (the macrophage) comes to the rescue. Whilst working on the repair, the breakdown service put barriers up around the car (increasing the size of the plaque). In the meantime, other nosey people in their cars (the blood) slow down to see what’s happened on an already narrowed road (reducing blood flow). With no traffic getting through, the road comes to a bit of a stand-still due to it being clogged up. In terms of your arteries, this means less oxygen and nutrients can reach their target organs.
So how does RCAN1 fit into this?
RCAN1 is a protein known to effect cellular migration and the shape of vessels, so is thought to be implicated in atherosclerosis progression. Upon comparison of atherosclerotic and non-atherosclerotic coronary arteries, it was shown that RCAN1 levels were higher in the arteries with atherosclerosis. To test this further, a mouse model was used: Apoe-/-. ApoE is a protein which regulates the transport of cholesterol, and does not function (is knocked out) in Apoe-/- mice. These mice spontaneously develop atherosclerosis and their plaques get larger and more numerous when fed a high cholesterol diet. A comparison of the levels of RCAN1 was made in three groups of mice:
(i) Apoe-/- mice fed a high cholesterol diet
(ii) Normal mice fed a normal diet and
(iii) Apoe-/- mice fed a normal diet
It showed that Apoe-/- mice fed a high cholesterol diet had more RCAN1 expression than the other two groups. This suggests RCAN1 is responsible for the atherosclerosis seen in the mice and mediates its effects through high cholesterol levels.
RCAN1 is also involved in affecting the size and severity of the plaques. Using Apoe-/- mice genetically engineered to have no RCAN1 (Apoe-/- Rcan1-/-), it was observed that these mice had smaller plaques than the Apoe-/- mice. In addition, Apoe-/- Rcan1-/- mice had less advanced plaques meaning that RCAN1 plays a pivotal role in the progression of the atherosclerotic plaque.
Finally, it was shown that the mice deficient in RCAN1 possessed macrophages that both have anti-inflammatory properties and have the ability to engulf LDL and move away from the plaque quicker, thereby easing plaque progression. That’s a bit like the breakdown service working a little faster to fix the car! Interestingly, when bone marrow cells deficient in RCAN1 were transplanted into Apoe-/- mice, plaque size and severity was decreased.
Handily, RCAN1 is 96% identical in mice and humans. This suggests that future atherosclerosis treatments might revolve around inhibiting RCAN1 or using haemopoetic stem cells that are deficient in RCAN1. As an increasingly common feature of our modern Western lifestyle, atherosclerosis and its associated problems aren’t going to disappear any time soon. But if we can develop treatments to inhibit RCAN1 there may be light at the end of the tunnel.
Méndez-Barbero N, Esteban V, Villahoz S, Escolano A, Urso K, Alfranca A, Rodríguez C, Sánchez SA, Osawa T, Andrés V, Martínez-González J, Minami T, Redondo JM, Campanero MR. (2013). A major role for RCAN1 in atherosclerosis progression EMBO Mol Med DOI: 10.1002/emmm.201302842