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Uncovering the Molecular Mechanism Behind Abdominal Aneurysms

In a recent paper, published in the journal JCI Insight, researchers from the University of Maryland School of Medicine (UMSOM) have revealed the molecular mechanism behind abdominal aortic aneurysms – the “silent killer” responsible for the death of Albert Einstein. Their hope is that this will lead to the discovery of risk genes in predisposed patients.

Tummy troubles

Abdominal aortic aneurysms (AAAs) are a bulge in the main artery that runs from the heart to the stomach. They are often caused by plaque build-up in the arteries, but sometimes by infection or even injury. If they are not spotted early, these aneurysms can burst – 5000 people die every year in the US because of ruptured AAAs. Preventative surgery can help combat the condition, but there is currently no way of screening to predict who might need to undergo this procedure. There are also no known genetic risk factors.

The main contributing factors towards the development of the condition are having high cholesterol or blood pressure, age, sex (being born a man), or being a smoker. “Certain genetic mutations may make someone more likely to have their repair process end up going haywire causing the portion of the artery to swell like a balloon and instead of healing a section of damaged artery,”said study co-author Jackie Zhang, Surgery Resident at UMSOM.

Looking at LRP1

In a healthy blood vessel, smooth muscle cells help to maintain vascular integrity by abundantly expressing the low-density lipoprotein receptor–related protein 1 (LRP1). This protein is a receptor that recognises a wide range of ligands – from lipoproteins to protease-inhibitor complexes.

The team were already aware that LRP1 was involved in a similar linked condition that occurs in the chest – thoracic aortic aneurysms. Based on this knowledge, they decided to create LRP1 knockout mice – these mice did not produce the LRP1 protein in their smooth muscle cells (the cells lining blood vessels). They then used CT scans to study the blood vessels and found that they were enlarged compared to the vessels in “normal” mice (Figure1).

Figure 1: Image shows 3D reconstruction of micro-CT images of superior mesenteric artery in “normal” and LRP1 knockout mice.

The next step was to find out what exactly was causing this abnormal enlargement. The team decided to use a global quantitative proteomic analysis of normal and diseased tissues, revealing 2,465 total proteins, of which 809 were significantly altered in the LRP1 negative mice. They found that the enlarged vessels had higher levels of certain proteins involved in the hormonal angiotensin-renin system – the system that regulates blood pressure and blood vessel growth and development. 

Translation to humans

Now they had their potential mechanism, it was time to test their theory. They showed that when they blocked an angiotensin receptor in the genetically engineered LRP1 negative mice using the drug losartan, it prevented the abdominal arteries from enlarging. Not only that, but they were also able to show that an alternative mechanism could similarly be used to prevent enlarged arteries – removing the precursor hormone to angiotensin in the liver.

“Our next step is to conduct human genetic studies on these newly identified mice components to see if we can find a genetic correlation in abdominal aneurysm patients. My gut feeling says that we will identify previously unknown genetic mutations associated with an increased risk of this condition,” said study leader Dudley Strickland, PhD, Professor of Surgery and Physiology, Director of the Center for Vascular & Inflammatory Diseases at UMSOM. “From there, we could screen people to identify those with an increased risk of developing abdominal aneurysms, have their physicians monitor them, and intervene when necessary to save lives.”

More on these topics

aneurysms / aorta / Genetics / risk genes