A strange case of immunosuppressive hypertension

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High blood pressure always leads to a weak heart.

Surprisingly, some patients with the PDE3A gene mutation were immune to the damage associated with high blood pressure.

Scientists in Berlin have been studying a strange genetic condition that causes half of the members of certain families to have shockingly short fingers and abnormally high blood pressure for decades. If not treated, individuals who have a stroke often die by the age of 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 (PDE3A) gene causes an increase in the activity of its enzyme, which alters bone growth and pathogenesis. In blood vessels swell, which leads to high blood pressure.

Immune to the damages associated with high blood pressure

“High blood pressure almost always leads to a weak heart,” says Dr. Ino Klausmann, Head of the Fixed Signals Laboratory at the Max Delbrück Center and a scientist at the German Center for Cardiovascular Research (DZHK). Klußmann explains that because it has to pump against a higher pressure, the organ tries to stiffen the left ventricle. “But ultimately, this leads to a thickening of the heart muscle — known as cardiomegaly — which can lead to heart failure and greatly reduce its pumping ability.”

Short fingers family of hypertension

Short fingers in the same family. Credit: Sylvia Baring

However, this does not occur 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 would normally result from high blood pressure,” says Klußmann.

The research was conducted by scientists from the Max Delbrück Centre, Charité – Universitätsmedizin Berlin, and DZHK and has been published in the journal Rotation. In addition to Klausmann, final authors included Max Delbrück Center professors Norbert Huebner and Michael Bader, as well as Dr Silvia Baring of the Experimental and Clinical Research Center (ECRC), a joint institution of Charity and the Max Delbrück Center.

The team, which includes 43 other researchers from Berlin, Bochum, Heidelberg, Kassel, Limburg, Lübeck, Canada and New Zealand, recently published their findings on the protective effects of a genetic mutation — and why these discoveries might change the way the heart works. Failure is dealt with in the future. The study includes four first authors, three of whom are researchers at the Max Delbrück Center and one at the European Research Center.

Normal heart vs altered heart

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

Two mutations have the same effect

The scientists carried out their tests on human patients with hypertensive muscular dystrophy (HTNB) syndrome — that is, high blood pressure and abnormally short numbers — as well as on mouse models and heart muscle cells. The cells were grown from specially designed stem cells known as induced pluripotent stem cells. Before starting testing, the researchers modified the PDE3A gene in cells and animals to mimic HTNB mutations.

“We encountered a previously unknown genetic mutation in PDE3A in the patients we examined,” reports Bähring. “Previous studies have always shown that the mutation in the enzyme is located outside the catalytic domain – but we have now found a mutation in the center of this domain.” Surprisingly, both mutations have the same effect in that they make the enzyme more active than normal. This hyperactivity increases the degradation of an important signaling molecule in the cell known as cAMP (cyclic adenosine monophosphate), which is involved in the contraction of heart muscle cells. “It is possible that this genetic modification — no matter where it is located — causes two or more PDE3A molecules to clump together and thus work more effectively,” Behring suspects.

The proteins remain the same

The researchers used a mouse model — which was created using 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 an agent isoproterenol, which is called a beta-receptor agonist,” Klossman says. Such drugs are sometimes used in patients with end-stage heart failure. Isoproterenol is known to cause enlargement of the heart. But surprisingly, this happened in the transgenic mice in a similar way to what we observed in wild animals. Contrary to what we would have expected, the current high blood pressure did not exacerbate the situation, ”says Klossmann. “It is clear that their hearts were protected from the effect of isoproterenol.”

In other experiments, the team studied whether proteins in a specific signaling chain of heart muscle cells changed as a result of the mutation, and if so which proteins. Through this chain of chemical reactions, the heart responds to adrenaline and beats faster in response to situations such as excitement. Adrenaline activates beta receptors in cells, which causes 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 mice in both protein and

RNA
RNA is a polymeric molecule similar to DNA and is essential in various biological roles in the coding, decoding, regulation and expression of genes. Both are nucleic acids, but unlike DNA, RNA is single-stranded. The RNA strand contains a backbone made up of alternating groups of sugar (ribose) and phosphate. Attached to each sugar is one of four bases – adenine (a), uracil (u), cytosine (c), or guanine (c). There are different types of RNA in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA), and transporter RNA (tRNA).

“data-gt-translate-attributes=”[{” 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


#strange #case #immunosuppressive #hypertension

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