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Perspective: A tale of two receptors

A hormone system adapted for self-preservation can break and fix your heart, say Sébastien Foulquier, Ulrike Muscha Steckelings and Thomas Unger.

Imagine someone cut severely in an accident and losing blood fast. Blood pressure drops dangerously low as blood is lost, and the kidneys react by releasing the enzyme renin. The circulating renin leads to the production of angiotensin II, a hormone that constricts blood vessels and prompts the kidneys to retain more salt and water to prop up the blood pressure. This renin–angiotensin system can save the life of our imagined person as they lay bleeding to death. Under other circumstances, it can kill. Our research reveals that the renin–angiotensin system might be tweaked in novel ways to fight heart disease — but we can only do that accurately and precisely by first learning the exact details of how the system's hormone receptors work.

The consequences of activating the renin–angiotensin system depend on the circumstances, and to which receptor the angiotensin II binds. If it binds to the angiotensin AT1 receptor, the blood pressure-increasing mechanism is engaged. And AT1 receptor binding under normal circumstances can raise blood pressure and damage the cells of the heart's left ventricle, the chamber that pumps oxygenated blood out of the heart. In addition, clinical studies have shown that drugs that block this receptor can also reduce damage to the heart. Therefore, blocking this receptor serves as a therapeutic strategy for treating cardiovascular diseases, especially hypertension.

When drugs for high blood pressure block a receptor docking site for angiotensin II, more of the hormone remains free to circulate in the blood. Increased levels of circulating angiotensin II affect a second receptor, AT2. The AT2 receptor triggers a molecular cascade that expands the size of blood vessels and helps prevent damage to the heart. In essence, the actions triggered by the second receptor are the opposite of the processes caused by the first. In addition, the body makes more AT2 receptors in response to several pathological conditions, including heart attack, heart failure and stroke. So when things go wrong with the cardiac system, the AT2 receptor system appears to serve a protective function.

Other research results support such a protective role for the AT2 receptor. In one study, for example, researchers engineered animals with varying amounts of AT2 receptor and confirmed that it can activate mechanisms that protect the heart1 (some studies produced conflicting results, possibly due to different receptor production levels in the genetically altered animals). As well as modifying the amount of the receptor, researchers can look for molecules other than angiotensin II that can turn on the AT2 receptor. Just such a molecule exists, and it's called compound 21 (C21).

We and other research groups have tested C21's ability to influence high blood pressure, but surprisingly C21 has no effect on the condition2. Nonetheless, our results continue to suggest the potential of exploiting this compound's role in repairing an injured heart. For example, C21 reduces stiffness in arteries, an effect that could indirectly affect blood pressure3,4. Moreover, in an animal model of a heart attack, in which blood flow to the heart is stopped, causing muscle damage or even death, administered C21 improves cardiac function and reduces scarring to cardiac tissue5. These benefits arise from C21's anti-inflammatory properties and its canny ability to keep cardiac cells from dying. And both result from the compound binding to AT2 receptors. Other findings suggest that C21 can improve heart health in even more ways. In human cardiac stem cells, for example, stimulating the AT2 receptors slows the death of heart muscle cells6. Likewise, activating AT2 receptors bound to immune cells in specific parts of the heart makes these cells fight inflammation, thereby protecting the heart7.

The same mechanism that helps respond to haemorrhage can also, under different circumstances, damage the heart.

The renin–angiotensin system illustrates the complexity of molecular pathways that can help and hinder the heart. The same mechanism that helps respond to haemorrhage can also, under different circumstances, damage the heart. Conversely, using this same system to trigger a different pathway — through a different receptor — repairs heart damage. As scientists explore this pathway through C21, we keep learning more about the molecular mechanisms behind this complex system. Perhaps combining conventional medication for high blood pressure with drugs developed around the AT2 receptor will provide us with new ways to preserve heart function. As we also now know, even more pathways originate in the renin–angiotensin system, pathways that may lead to future heart medications. But first, we must understand the receptors that mediate it all.

References

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Correspondence to Sébastien Foulquier.

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Ulrike Muscha Steckelings declares a conflict of interest. She received research support from Vicore Pharma, which developed compound 21.

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Foulquier, S., Steckelings, U. & Unger, T. Perspective: A tale of two receptors. Nature 493, S9 (2013). https://doi.org/10.1038/493S9a

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