PCSK9

Estimated reading time: 7 minutes

These are exciting times for the field of cardiovascular medicine.

Despite huge improvements in risk factor modification and progress in medical and surgical therapy, cardiovascular disease remains the most frequent cause of death among most nations. However, increased understanding of the mechanisms behind atherosclerosis, the role of lipoproteins, inflammation and other factors, has opened gates to new targets for treatment.

A protein called PCSK9 received huge attention at the American Heart Association’s annual meeting in Los Angeles earlier this week. The role of PCSK9 in lipoprotein clearance has been quite well defined and it’s availability in the blood stream may significantly affect our risk of heart disease.

Lipoproteins

The insolubility of lipids in water poses a problem because lipids must be transported through aqueous compartments within the cell as well as in the blood and tissue spaces. Lipoproteins are biochemical structures that enable transport of lipids throughout the body. A lipoproetein includes a core, consisting of a droplet of triacylgycerols and/or cholesterlyl esters, a surface layer of phospholipid, unesterified cholesterol and specific proteins (apolipoproteins). Lipoprotein particles are commonly classified according to their density, thus the terms high density lipoprotein (HDL) and low density lipoprotein (LDL). Apolipoprotein B is the primary lipoprotein in LDL.

Chylomicrons are primarily triglyceride-bearing lipoproteins produced after meal. VLDLs are produced by the liver with a primary function of supplying free fatty acid to tissues and they are the main carriers of triglycerides. LDL’s are by-products of VLDL metabolism and are the primary carriers of plasma cholesterol. Chylomicrons, VLDL and LDL all carry apolipoprotein B (apoB), among other lipoproteins. HDL’s carry apoAI and apoAII. Within each category, there is a spectrum of particles that vary in size, density and relative proportions of lipid and protein.

Atherosclerosis and LDL

Atherosclerosis is a form of chronic inflammation resulting from complex interactions between lipoproteins, white blood cells (macrophages), different components of the immune system and the normal elements of the arterial wall.

This process can lead to formations of atherosclerotic lesions or plaques that may protrude into the lumen of the artery causing arterial narrowing which may ultimately limit blood flow. If this occurs in the coronary arteries, it may cause symptoms commonly known as angina pectoris and if it occurs in the leg arteries it may cause claudication. Rupture of an atherosclerotic plaque may lead to thrombosis causing an acute occlusion of the artery. If this occurs in a coronary artery it may lead to an acute myocardial infarction.

There are many factors that contribute to atherosclerosis, one of which is elevated of levels cholesterol. Although cholesterol is an essential compound, elevated plasma levels appear to play an important role in the initiation and progression of atherosclerosis. In animal models, atherosclerosis will not occur in the absence of greatly elevated levels of plasma cholesterol.

High levels of plasma cholesterol also appears to be an important contributor to atherosclerosis in humans, although the threshold level of plasma cholesterol that must be exceeded to produce clinically relevant disease appears to be much lower than that in animal models, possibly because lesion formation occurs over many decades. Atherosclerotic clinical events are uncommon among individuals with lifelong very low plasma cholesterol levels.

It must be emphasized however, that it is lipoprotein that interact with the arterial wall and initiate the cascade of events that leads to atherosclerosis. Cholesterol is only one of many components of lipoproteins.  A causative role for cholesterol in itself has never been proven, although it appears that atherosclerosis will not occur without this compound.

Measurements of total cholesterol are only indirect measurements of the lipoproteins that transport the bulk of cholesterol and are the most atherogenic. Indeed, measurements of the number of LDL-particles (LDL-P) appear more predictive of risk than the measurements of the cholesterol mass within these particles (LDL-C). Although LDL’s seem to be the most atherogenic particles, it has to remembered that VLDL and other apoB – containing lipoproteins may also contribute to atherosclerosis.

The liver is the gatekeeper for LDL and is responsible for its clearance. Liver cells express LDL-receptors on their surface, that bind LDL and remove it from the blood stream. After binding to the LDL-receptor, the LDL/LDL-receptor complex is moved to endosomes within the liver cells, where the LDL is released from the complex. The LDL receptor then moves back to the cell surface where it can bind to additional LDL-particles. This circle leads to removal of LDL-particles from the circulation which can be measured as a reduction in LDL-cholesterol levels. The free LDL left within the cells is transported to lysosomes and degraded into lipids, free fatty acids and amino acids.

PCSK9

PCSK9 (Proprotein convertase subtilisin-like/kexin type 9) is a protein that regulates the expression of LDL-receptors in the liver. PCSK9 is produced by liver cells and released into the blood stream. PCSK-9 binds to the LDL-receptor on the surface of liver cells, together with LDL. It moves into the cell, together with the LDL-receptor/LDL complex. After LDL is released from this complex, the LDL – receptor/PCSK9 complex is taken up by lysosomes for degradation, preventing the recycling of the LDL-receptor to the cell surface. Thus, PCSK9 is responsible for the degradation of LDL-receptors and therefore plays a critical role in the regulation of LDL-cholesterol levels.

Interestingly, mutations on the human PCSK gene expression that lead to a loss of PCSK9 function are found in 1 – 3 percent of the population. These mutations have been associated with lower LDL-cholesterol levels and a significantly lower incidence of coronary heart events. Inhibition of the interaction between PCSK9 and the LDL receptor may potentially lower LDL-cholesterol levels.

A monoclonal antibody directed against PCSK9 could potentially lower LDL cholesterol if it blocks the interaction of PCSK9 with the LDL-receptor on the surface of liver cells. This may allow LDL- receptors to recycle to the cell surface, after releasing LDL within the cell, instead of being taken up and degraded in lysosomes. Increased concentration of LDL receptors on the surface of liver cells may lead to increased clearance of LDL, which will be reflected as reduced levels of LDL-cholesterol.

Three new phase 2 studies with two anti-PCSK monoclonal antibodies were presented at the American Heart Association´s annual meeting in Los Angeles earlier this week.

These studies showed large reductions in LDL-cholesterol with or without concurrent statin therapy. Dr Peter Wilson (Emory University School of Medicine, Atlanta) said the studies indicated that these new monoclonal antibodies “are very effective and extremely promising”. He added: “All eyes will be on safety and long-term outcomes.” He noted that adverse events so far reported suggest some myalgia (muscle pain) and creatinine-kinase (CK) elevation. Dr Frederick Raal (University of Witewatersrand, Johannesburg, South Africa) said: “If you believe in LDL-lowering, then these drugs will help us”.

The Future

Large-scale phase three trials will be starting soon in patients with known cardiovascular disease, where  monoclonal antibodies to PCSK9, or corresponding placebo will be added on top of statin therapy. These antibodies are given by subcutaneous injection.

Interestingly, the studies will not only test the clinical efficacy of these particular drugs, they will also further test the much debated lipid hypothesis.

The lipid hypothesis is based on the association between cholesterol, LDL-cholesterol in particular, and the risk of cardiovascular disease.

Statins have been shown to reduce mortality and the risk of cardiovascular events in patients with cardiovascular disease. However, it has been debated whether this is due to the lowering of LDL-cholesterol or by some other (pleiotropic) effects of these drugs.

The JUPITER trial showed positive effects of statin therapy in patients with normal or low LDL-cholesterol but signs of inflammation (elevated hs-CRP), suggesting that the anti-inflammatory effects of statins may be important.

A clinical study is currently in progress, testing the efficacy of anti-inflammatory agents in patients with coronary heart disease and elevated hs-CRP. Hopefully, these scientific studies will increase our understanding of the role of LDL-cholesterol and inflammation respectively in the progression of cardiovascular disease.