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A bizarre case of hypertensive immunity

Human Heart Attack
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High blood pressure almost always causes heart failure.

Surprisingly, certain patients with the mutated PDE3A gene were immune to hypertension-related damage.

Scientists in Berlin are studying a strange genetic disorder that has left half the people in certain families with shockingly short fingers and abnormally high blood pressure for decades. Left untreated, those affected often die of a stroke at the age of 50. Researchers at the Max Delbrück Center (MDC) in Berlin discovered the origin of the disease in 2015 and were able to verify it in an animal model five years later: a mutation in the phosphodiesterase 3A gene (PDE3A) causes its encoded enzyme to become overactive, which causes bone growth changed and causes blood vessel hyperplasia, leading to high blood pressure.

Immune to hypertension-related damage

“High blood pressure almost always causes the heart to weaken,” says Dr. Enno Klußmann, head of the Anchored Signaling Lab at the Max Delbrück Center and scientist at the German Center for Cardiovascular Research (DZHK). Since it has to pump against a higher pressure, Klußmann explains, the organ is trying to strengthen its left ventricle. “But ultimately this leads to thickening of the heart muscle — known as cardiac hypertrophy — which can lead to heart failure, which severely reduces its ability to pump blood.”

Short finger hypertension family

Short fingers in a family. Photo credit: Sylvia Bähring

However, this does not occur in hypertensive patients with short fingers and mutated PDE3A genes. “For reasons that are now partially – but not fully – understood, their hearts appear to be immune to the damage normally caused by high blood pressure,” says Klußmann.

The research was carried out by scientists from the Max Delbrück Center, the Charité – Universitätsmedizin Berlin and the DZHK and published in the journal Traffic. In addition to Klußmann, the final authors included the Max Delbrück Center professors Norbert Hübner and Michael Bader as well as Dr. Sylvia Bähring from the Experimental and Clinical Research Center (ECRC), a joint institution of the Charité and the Max Delbrück Center.

The team, which included 43 other researchers from Berlin, Bochum, Heidelberg, Kassel, Limburg, Lübeck, Canada and New Zealand, recently published their findings on the protective effects of the gene mutation – and why these discoveries could change the way heart failure is diagnosed in treated future. The study has four first authors, three of whom are researchers at the Max Delbrück Center and one at the ECRC.

Normal heart vs. mutant heart

Cross sections through a normal heart (left), through one of the mutated hearts (middle) and through a severely hypertrophic heart (right). In the latter, the left ventricle is enlarged. Credit: Anastasiia Sholokh, MDC

Two mutations with the same effect

The scientists carried out their tests on human patients with hypertension and brachydactyly (HTNB) syndrome – i.e. high blood pressure and abnormally short fingers – as well as on rat models and heart muscle cells. The cells were grown from specially engineered stem cells known as induced pluripotent stem cells. Before starting the tests, the researchers altered the PDE3A gene in the cells and the animals to mimic HTNB mutations.

“We found a previously unknown PDE3A gene mutation in the patients we examined,” reports Bähring. “Previous studies had always shown that the mutation in the enzyme is outside the catalytic domain – now we have found a mutation right in the center of this domain.” Surprisingly, both mutations have the same effect, making the enzyme more active than usual. This hyperactivity accelerates the breakdown of an important cell signaling molecule known as cAMP (cyclic adenosine monophosphate), which is involved in the contraction of heart muscle cells. “It is possible that this genetic modification – regardless of its location – leads to two or more PDE3A molecules merging and thus working more effectively,” suspects Bähring.

The proteins stay the same

The researchers used a rat model – created using CRISPR-Cas9 technology from Michael Bader’s lab at the Max Delbrück Center – to try to better understand the effects of the mutations. “We treated the animals with the active ingredient isoproterenol, a so-called beta-receptor agonist,” says Klußmann. Such drugs are sometimes used in patients with end-stage heart failure. Isoproterenol is known to induce cardiac hypertrophy. “Surprisingly, this occurred in the genetically modified rats in a similar way to what we observed in the wild-type animals. Contrary to our expectations, the existing high blood pressure has not made the situation worse,” reports Klußmann. “Their hearts were obviously protected from this effect of the isoproterenol.”

In further experiments, the team investigated whether proteins in a specific signaling cascade of heart muscle cells had changed as a result of the mutation, and if so, which ones. Through this chain of chemical reactions, the heart responds to adrenaline and beats faster in response to situations such as excitement. Adrenaline activates the cells’ beta receptors, causing them to produce more cAMP. PDE3A and other PDEs stop the process by chemically altering cAMP. “However, we found hardly any differences between mutant and wild-type rats in terms of both protein and protein[{” attribute=””>RNA levels,” Klußmann says.

More calcium in the cytosol

The conversion of cAMP by PDE3A does not occur just anywhere in the heart muscle cell, but near a tubular membrane system that stores calcium ions. A release of these ions into the cytosol of the cell triggers muscle contraction, thus making the heartbeat. After the contraction, the calcium is pumped back into storage by a protein complex. This process is also regulated locally by PDE.

Klußmann and his team hypothesized that because these enzymes are hyperactive in the local region around the calcium pump, there should be less cAMP – which would inhibit the pump’s activity. “In the gene-modified heart muscle cells, we actually showed that the calcium ions remain in the cytosol longer than usual,” says Dr. Maria Ercu, a member of Klußmann’s lab and one of the study’s four first authors. “This could increase the contractile force of the cells.”

Activating instead of inhibiting

“PDE3 inhibitors are currently in use for acute heart failure treatment to increase cAMP levels,” Klußmann explains. Regular therapy with these drugs would rapidly sap the heart muscle’s strength. “Our findings now suggest that not the inhibition of PDE3, but – on the contrary – the selective activation of PDE3A may be a new and vastly improved approach for preventing and treating hypertension-induced cardiac damage like hypertrophic cardiomyopathy and heart failure,” Klußmann says.

But before that can happen, he says, more light needs to be shed on the protective effects of the mutation. “We have observed that PDE3A not only becomes more active, but also that its concentration in heart muscle cells decreases,” the researcher reports, adding that it is possible that the former can be explained by oligomerization – a mechanism that involves at least two enzyme molecules working together. “In this case,” says Klußmann, “we could probably develop strategies that artificially initiate local oligomerization – thus mimicking the protective effect for the heart.”

Reference: “Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage” by Maria Ercu, Michael B. Mücke, Tamara Pallien, Lajos Markó, Anastasiia Sholokh, Carolin Schächterle, Atakan Aydin, Alexa Kidd, Stephan Walter, Yasmin Esmati, Brandon J. McMurray, Daniella F. Lato, Daniele Yumi Sunaga-Franze, Philip H. Dierks, Barbara Isabel Montesinos Flores, Ryan Walker-Gray, Maolian Gong, Claudia Merticariu, Kerstin Zühlke, Michael Russwurm, Tiannan Liu, Theda U.P. Batolomaeus, Sabine Pautz, Stefanie Schelenz, Martin Taube, Hanna Napieczynska, Arnd Heuser, Jenny Eichhorst, Martin Lehmann, Duncan C. Miller, Sebastian Diecke, Fatimunnisa Qadri, Elena Popova, Reika Langanki, Matthew A. Movsesian, Friedrich W. Herberg, Sofia K. Forslund, Dominik N. Müller, Tatiana Borodina, Philipp G. Maass, Sylvia Bähring, Norbert Hübner, Michael Bader and Enno Klussmann, 19 October 2022, Circulation.
DOI: 10.1161/CIRCULATIONAHA.122.060210

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