A bizarre case of immunity to hypertension


High blood pressure almost always causes a weakening of the heart.

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

Scientists in Berlin have for decades been studying a strange inherited condition that causes half of people in some families to have incredibly short fingers and abnormally high blood pressure. Left untreated, those affected often die of strokes by the age of 50. Researchers from the Max Delbrück Center (MDC) in Berlin discovered the origin of the disease in 2015 and were able to verify it five years later using animal models: a mutation in the phosphodiesterase 3A (PDE3A) gene causes its enzyme coded becomes hyperactive, impairing bone growth and causing hyperplasia of blood vessels, resulting in increased blood pressure.

Immune to damage related to hypertension

“High blood pressure almost always leads to a weakening of the heart,” 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). Because it has to pump against higher pressure, explains Klußmann, the organ tries to strengthen its left ventricle. “But ultimately, this results in thickening of the heart muscle — known as cardiac hypertrophy — which can lead to heart failure by greatly decreasing its pumping ability.”

Short finger hypertension family

Short fingers in a family. Credit: Sylvia Bahring

However, this is not the case 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 conducted by scientists from the Max Delbrück Center, Charité – Universitätsmedizin Berlin and DZHK and was published in the journal circulation. In addition to Klußmann, the final authors included Max Delbrück Center professors Norbert Hübner and Michael Bader, as well as Dr. Sylvia Bähring from the Center for Experimental and Clinical Research (ECRC), a joint institution of 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 findings could transform the way the heart failure is 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 versus mutant heart

Cross-section of a normal heart (left), one of the mutant hearts (middle), and a severely hypertrophied heart (right). In the latter, the left ventricle is enlarged. Credit: Anastasiia Sholokh, MDC

Two mutations with the same effect

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

“We came across a previously unknown PDE3A gene mutation in the patients we examined,” reports Bähring. ‘Previous studies have always shown that the mutation in the enzyme is outside the catalytic domain, but now we have found a mutation right in the middle of this domain.’ Surprisingly, both mutations have the same effect as they make the enzyme more active than usual. This overactivity 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 heart muscle cells. “It is possible that this genetic modification, regardless of its location, causes two or more PDE3A molecules to clump together and thus function more effectively,” suspects Bähring.

The proteins stay the same

The researchers used a rat model, created with CRISPR-Cas9 technology by 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 agent 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. “However, surprisingly, this occurred in genetically modified rats in a similar way to what we have observed in wild animals. Contrary to what we expected, the existing high blood pressure did not aggravate the situation,” reports Klußmann. “Their hearts were obviously protected against this effect of isoproterenol.”

In further experiments, the team investigated whether proteins in a specific heart muscle cell signaling cascade 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 beta receptors of cells, causing them to produce more cAMP. PDE3A and other PDEs interrupt the process by chemically altering cAMP. “However, we found little difference between mutant and wild-type rats for either the protein or the

Activate instead of inhibit

“PDE3 inhibitors are currently being used for the treatment of acute heart failure to increase cAMP levels,” explains Klußmann. Regular therapy with these drugs would rapidly weaken the strength of the heart muscle. “Our results now suggest that not PDE3 inhibition, but – on the contrary – selective PDE3A activation could be a new and greatly improved approach to prevent and treat hypertension-induced heart damage such as hypertrophic cardiomyopathy and L ‘heart failure,’ says Klußmann. .

But before that can happen, he says, more light needs to be shed on the protective effects of the mutation. “We observed that PDE3A not only becomes more active, but also that its concentration in heart muscle cells decreases,” reports the researcher, adding that it is possible that the former could be explained by oligomerization, a mechanism involving 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 UP 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, October 19, 2022, circulation.
DOI: 10.1161/CIRCULAZIONEAHA.122.060210

Leave a Comment

%d bloggers like this: