Hidden Secrets Of The Heart

The plot thickens… and so does the artery wall!

By Sophie Quick

A  Nature  paper  published in December last year showed that clues to your future health may already be hidden in your genome. The team behind the work was looking to identify whether particular mutations in particular genes might correlate with early-onset heart attack.

Each protein in your body is coded for by a specific gene.  If we look across an entire population, the code is a fairly synonymous in everyone, but we can see discrepancies in the code – mutations – that disrupt it and lead to faulty proteins. Such mutations are rare and once identified in a particular individual we can correlate them with any diseases they present, either at the time or in their patient history. If more individuals share these mutations and disease traits they could indicate a group whose incidence of a certain disease may be raised by the mutations they carry. In this way, we can say certain mutations confer risk for a certain disease.

The  Nature  paper looked at the protein-encoding portions of nearly 10,000 people that had suffered a heart attack at an early age, to see whether any mutations were significantly more common when compared to a control group. For men an early-onset heart attack was classed as under 50 years of age and for women it was under 60 years.

Two of the genes sequenced showed rare mutations that were more common in the heart attack group. One encodes apo-lipoprotein A-V (APOA5) and the other encodes the low-density lipoprotein receptor (LDLR). Given the roles these proteins play in the body, these data reveal new genes posing as potential risk factors for cardiovascular disease lurking in the genome, and suggests they pose important influence in early-onset heart attack.

The plot thickens… and so does the artery wall

APOA5 encodes a protein that has the job of binding lipids to form lipoproteins. Lipids are molecules like fat, cholesterol and triglycerides that dissolve in oil and can only be transported around the body in the blood with the use of these lipoproteins. APOA5 is a structural component of the lipoprotein particle and is thought to interact with LDLR proteins.

The LDLR protein sits on the surface of cells and its job is to internalize low density lipoprotein (the “bad” kind of cholesterol). The LDLR scavenges LDL from the blood and so regulates the levels of blood cholesterol. A poorly functioning LDLR is therefore linked to the build-up of LDL-cholesterol in blood vessel walls. Accumulation of LDL in major blood vessels leads to atherosclerosis – thickening of the artery walls – which is responsible for the majority of cardiovascular events.

In the Nature paper, the blood samples of those carrying the rare mutations were also examined for the levels of certain lipids to support the theory above.  Compared to controls, people with mutations in APOA5 also had higher levels of triglycerides in their blood, and people with mutations in LDLR had higher serum levels of LDL cholesterol. This suggests that there is an incorrect breakdown of lipoproteins for these mutation carriers, possibly leading to increased atherosclerosis. The increased risk for heart attack caused by these mutations may be due to protein malfunction in lipid transport pathways. 

A closer look at the suspects…

Further investigation of the two proteins identified could help define their role in lipoprotein breakdown, and potentially uncover therapeutic targets for preventing atherosclerosis and other cardiovascular diseases. Targeting these proteins with specific antibodies (such as those available from Proteintech) enables researchers to study their role in certain disease processes. 

An example of  such work comes from a different paper published earlier in 2014, which demonstrated how increased production of LDLR could lead to atherosclerosis.  This team was looking to identify the mechanism by which another protein tumor necrosis factor-α (TNF-α) caused a build-up of lipoproteins in blood vessels. They proposed it did so by increasing LDL movement across blood vessel epithelial cells in a process called transcytosis. They also wanted to determine the molecular pathway involved.

Fluorophore labeling of LDL and fluorescence imaging techniques showed that its movement through the plasma membrane was indeed increased by stimulating TNF-α. They then showed the production of proteins involved in transcytosis, including LDLR – using the Proteintech anti-LDLR antibody to conduct Western blot analysis. This demonstrated that TNF- α might increase the levels of LDL movement by increasing the expression of LDLR and other related proteins.

What’s next for LDLR and APOA5…

Clearly, LDLR and APOA5 have key roles in lipoprotein regulation as, upon their mutation, they bring about changes in blood lipid levels and an increased risk of heart attack. They may turn out to be valuable clinical markers for recognizing patients at risk of early-onset heart attack in a population. They may also enable scientists to design potential therapeutic targets for the prevention or treatment of a number of cardiovascular diseases that pose a huge burden on society.

Related Products

Antibody name Catalog number Type Applications
LDLR 10785-1-AP Rabbit poly ELISA, WB, IHC, IP
APOA5 65015-1-Ig Mouse mono ELISA, WB

Guest Blogger Profile

Sophie Quick is a Biology undergraduate at the University of York. Following spending a year in industry at AstraZeneca (AZ), she is completing her final year, currently building a cell line model of bone disease using gene knockout technology. During her AZ placement year she developed 3D cell culture methods for use in high-throughput screening. Currently cultivating a love of science communication as well as research, she plans to continue on to a PhD to pursue her interests in stem cell biology and regenerative medicine. Her main hobby is making science-themed baked goods… and eating them. Suggestions welcome: @SophieFQuick

References 

R. Do et al., Nature. 2014 Dec 10. doi: 10.1038/nature13917. [Epub ahead of print]

Y. Zhang et al., J Mol Cell Cardiol. 2014 Jul;72:85-94

 

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Posted:
12 August, 2016

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