A scientific breakthrough on the control of the bad cholesterol

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A scientific breakthrough on the control of the bad cholesterol

http://www.eurekalert.org/pub_releases/2008-11/idrc-asb112408.php

A study performed by the team of Dr. Nabil G. Seidah, Director of the

Biochemical Neuroendocrinology Research Unit at the IRCM, shows for

the very first time that the degradation by PCSK9 of the LDLR

receptor, which is responsible for removing the bad cholesterol (LDL-

cholesterol) from the bloodstream, may be inhibited by a third

protein, annexin A2. This major discovery co-authored by Gaétan

Mayer, a postdoctoral fellow, Steve Poirier, a doctoral student, and

Dr. Seidah was published on November 14 in the Journal of Biological

Chemistry (JBC).

Genetic studies on humans have clearly shown that PCSK9 is a prime

therapeutic target for the prevention and treatment of cardiovascular

diseases. PCSK9 proprotein convertase promotes the degradation of the

receptor responsible for eliminating LDL-cholesterol particles. Thus,

the presence of PCSK9 leads to a surplus of bad cholesterol in the

bloodstream and contributes to plaque formation, leading to blockage

of blood vessels and arteries. This phenomenon is a major risk factor

that can lead to cardiovascular diseases, such as heart attack,

atherosclerosis and stroke. Mutations of human genes have

demonstrated that a rise in PCSK9 activity results in a major

increase in LDL-cholesterol and familial hypercholesterolemia.

Conversely, in people with a non-functional mutation in the gene

coding for PCSK9, a decrease in its activity brings down the LDL-

cholesterol concentration levels in the bloodstream and diminishes by

up to 88% the risks of developing cardiovascular diseases.

" By performing a series of biochemical experiments, we discovered

that annexin A2 binds strongly to PCSK9 and inhibits its function, "

remarks Gaétan Mayer, the article's first author. This discovery

should pave the way toward the development of a new drug that would

lower blood cholesterol to recommended levels. Currently, cholesterol

lowering drugs known as " statins " are used by more than 25 million

people worldwide. Statins decrease cholesterol synthesis and increase

the number of LDL-receptors, thus efficiently decreasing plasma

cholesterol levels; however, they also increase the amount of PCSK9,

which degrades those receptors, thus reducing the effect of statins.

A drug that would block PCSK9 could either be used alone or jointly

with statins and would be highly beneficial to patients in whom

statins do not work or are unable to take this drug.

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This work was supported by the Canadian Institutes of Health Research

(CIHR) and by a Canada Research Chair.

Reference: Mayer G, Poirier S, and Seidah NG. (2008) Annexin A2 is a

C-terminal PCSK9-binding protein that regulates endogenous low

density lipoprotein receptor levels. J Biol Chem, November 14; 283

(46): 31791-801.