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ANGie

Photo by Morning Calm Weekly Newspaper Installation Management Command, U.S. Army

What makes your blood pressure raise? Beyond watching your favourite sports team do something infuriatingly stupid, or seeing someone reverse into your car, what make it go up? Or down? There are, like most parts of the gloriously complicated human body, lots of contributing factors; but one of the most significant is your Renin-Angiotensin System, or RAS for short (and sometimes RAAS). RAS is a homoeostatic system in your body contributing to keeping your insides in balance. However, despite this essential role some of RAS’s components also cause some less than friendly effects.

Angiotensin, generally referred to as ANG, is a type of hormone which causes vasoconstriction. Vasoconstriction is the shrinking of blood vessels, such as arteries, to increase blood pressure; low blood pressure can result in feints and organs not receiving enough blood. The formation of ANG happens thanks to the actions of the enzyme Renin, which is named after the part of the body (the renal system) in which it was first found in 1898 by the fabulously named Finnish scientists, Tigerstedt and Bergman. The ANGs themselves were not found until the twentieth century.

ANG comes in varieties I to IV which can be found throughout your body. I and II have in recent years been found to be implicated in a range of problems that the body might suffer, predominantly, though not exclusively, related to blood pressure. ANG II has been investigated extensively in relation to hypertension (high blood pressure) as high blood pressure is strongly associated with heart attacks, strokes and kidney disease.

In experiments, with some rather unfortunate mice, the team of Pharmacologist Lisa Cassis found that being infused (think mouse tea) in ANG II resulted in an increase in mean arterial pressure. Added to this the ANG II mice were also suffering from a rather disgusting problem known as atheroscleroitic leisions, where artery walls become thicker with fat deposits and “gruel”, and ultimately suffered from abdominal aortic aneurysms. The AAAs are, in humans, one of the most common forms of aneurysm in men past sixty; often causing no noticeable symptoms to the unfortunate man, or mouse, they can kill in minutes. The team then attempted treating their mice with a drug to counteract the constricting properties (Hydralazine), this did reduce the blood pressure, but sadly it didn’t prevent either the leisions or the aneurysms.

When not occupied with helping to kill off old men ANG II is also causing problems for the more corpulent amongst us. Many people who are seriously overweight will suffer from problems with thrombosis and blood clots. Skurk, Lee and Hauner found that ANG II promotes the production of PAI-1. PAI-1, otherwise known as Plasminogen Activator Inhibitor 1, prevents the proteins used to break down blood clots from working. Clotting is an essential function, without it we’d be haemorrhaging all over the place, but there needs to be enough blood flowing and not all trapped in one place to keep the body working. They found that ANG II results in adipose tissue, that is fat tissue, releasing PAI-1, leading to a lot of discomfort, and some very ugly compression socks. However, ANG II works via the AT1 receptors, and they found that blocking the receptor AT1 diminishes ANG II’s stimulation of PAI-1.

Making similar use of the receptors in their work, an Italian research team led by Benigni found that if they disrupted the gene which encodes the receptor, their study mice had a very good outcome. The mice not only had reduced cardiac and vascular problems, but their organs suffered less oxidative damage, and their kidneys had increased levels of the protein Sirtuin 3. Sirtuin 3 influences ageing and programmed cell breakdown (apoptosis), with the result that the study mice lived longer than their control contemporaries. The researchers confirmed ANG II’s effect on Sirtuin 3 by testing it outside of the mice, and found that ANG II did indeed reduce the functioning of this survival promotion protein. However, before you excitedly run off to the nearest lab to switch off human ANG receptors, Physiologist Lisa M. Harrison-Bernard reports that there is growing evidence that ANG II doesn’t need to stimulate the receptors to effect cells…

Whilst ANG I on the other hand has been found to have implications in the seemingly unrelated conditions of motor neurone disease and cancer.

French researchers studying familial Amytrophic Lateral Sclerosis (ALS), often known as Lou Gehrig’s disease (after the Yankees player who died from it), screened 162 families with known ALS. For comparison they also took samples from 500 controls. Though ANG I wasn’t the most populous mutation that they found in their results, that was the appropriately named SOD1, a ‘mis-sense’ ANG I mutation was found. Meaning that somewhere along the code for the gene that produces ANG I, one of the letters had been replaced with another, resulting in an incorrect amino acid in the chain.

Whilst the mutation in ANG I seems to be implicated in ALS, ANG I in its non-mutated state seems to be the issue in the Hedgehog cancer pathway. The Hedgehog signalling system forms part of the embryonic development, and is named not for the cute spiky chaps, but for a fly gene. The signals have a very important role during development of a foetus, but if activated as an adult they can cause cancer, and have been linked to several. The team led by Nakamura found that ANG I was helping bone marrow cancer cells to develop their own blood supply, which is just the thing you don’t want cancer cells doing. However, the Hedgehog pathway has a known enemy, the product of the plant Veratrum californicum, known as cyclopamine, is known to disrupt the pathway. It gets its rather mythological name from the effect its interruption has on any foetus, a condition called Holoprosencephaly where the brain does not divide correctly and any foetuses that make it to birth often have just one eye. Though Cyclopamine has rather awful effects for the not yet born it was found to have more positive outcomes for the bone marrow cancer that they studied, finding that the ANG I levels were reduced, and the pathway was turned off.

So with all that the ANGs can do are you wondering if “AngI, AngII, ain’t it time we said goodbye?”
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Articles mentioned:
“SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype–phenotype correlations” by
Stéphanie Millecamps, François Salachas, Cécile Cazeneuve and team in
Journal of  Medical Genetics  2010

“ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice”
Lisa A. Cassis, Manisha Gupte, Sarah Thayer and team
American Physiological Society

“Disruption of the Ang II type 1 receptor promotes longevity in mice”
Ariela Benigni, Daniela Corna, Carla Zoja, Aurelio Sonzogni and team.
Journal of Clinical Investigation 2009

“Hedgehog Promotes Neovascularization in Pancreatic Cancers by Regulating Ang-1 and IGF-1 Expression in Bone-Marrow Derived Pro-Angiogenic Cells”
Kazumasa Nakamura, Junpei Sasajima, Yusuke Mizukami and team
PLos One

“Trapping intracellular ANG II to the proximal tubule: powerful in vivo effects on sodium handling and blood pressure”
Lisa M. Harrison-Bernard
American Journal Physiology: Renal Physiology 2011

“Angiotensin II and Its Metabolites Stimulate PAI-1 Protein Release From Human Adipocytes in Primary Culture”
Thomas Skurk, Yu-Mi Lee, Hans Hauner
Hypertension 2001

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About Lotte

Likes making a mess and arguing.

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This entry was posted on August 11, 2012 by in Biology, General Science, Medicine and tagged , , , , .

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