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A Bizarre Case of Hypertension Immunity

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High blood pressure almost always causes the heart to weaken.

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

Scientists in Berlin have been studying for decades a strange hereditary condition that causes half of the people in certain families to have shockingly short fingers and abnormally high blood pressure. If left untreated, affected individuals often die of a stroke by age 50. Researchers at the Max Delbrück Center (MDC) in Berlin discovered the origin of the condition in 2015 and were able to verify it five years later using animal models: a mutation in the phosphodiesterase 3A gene (PDE3A) causes the encoded enzyme to become overactive , bone growth changes and causes hyperplasia of the blood vessels, resulting in 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 a scientist at the German Center for Cardiovascular Research (DZHK). Because it has to pump against a higher pressure, Klußmann explains, the organ tries to strengthen its left ventricle. “But ultimately this results in the thickening of the heart muscle — known as cardiac hypertrophy — which can lead to heart failure, greatly reducing its pumping capacity.”

Short Finger Hypertension Family

Short fingers in one family. Credits: Sylvia Bahring

However, this does not happen in hypertensive patients with short fingers and mutant PDE3A genes. “For reasons that are now partially – but not yet fully – understood, their hearts seem immune to the damage that usually results from high blood pressure,” says Klußmann.

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

The team, made up of 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 are changing the way heart failure is being treated. treated in the future. The study has four first authors, three of whom are researchers from the Max Delbrück Center and one from the ECRC.

Normal heart vs. mutated heart

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

Two mutations with the same effect

The scientists conducted their tests on human patients with the syndrome of hypertension and brachydactyly (HTNB), ie high blood pressure and abnormally short fingers, as well as on rat models and heart muscle cells. The cells are grown from specially engineered stem cells known as induced pluripotent stem cells. Before testing began, researchers altered the PDE3A gene in the cells and animals to mimic HTNB mutations.

“We encountered a previously unknown PDE3A gene mutation in the patients we examined,” reports Bähring. “Previous studies had always shown that the mutation in the enzyme was outside the catalytic domain, but we have now found a mutation right in the middle of this domain.” Surprisingly, both mutations have the same effect by making the enzyme more active than normal. This hyperactivity accelerates the breakdown of one of the cell’s important signaling molecules, known as cAMP (cyclic adenosine monophosphate), which is involved in the contraction of the heart muscle cells. “It is possible that this gene modification – regardless of location – causes two or more PDE3A molecules to clump together and thus work more effectively,” Bähring suspects.

The proteins remain the same

The researchers used a rat model – created with CRISPR-Cas9 technology by Michael Bader’s lab at the Max Delbrück Center – to better understand the effects of the mutations. “We treated the animals with the drug 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 cause cardiac hypertrophy. “But surprisingly, in the gene-modified rats, this happened in a manner similar to what we saw in the wild-type animals. Contrary to what we expected, the existing hypertension did not exacerbate the situation,” reports Klußmann. were clearly protected against this effect of isoproterenol.”

In further experiments, the team investigated whether proteins in a specific signaling cascade of the heart muscle cells 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 little difference between mutant and wild-type rats on both the protein and the[{” 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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