Hypertension with less harm
Sometimes nature provides humans with good examples to work from, as in the case of families affected by the hereditary disease HTNB: some family members have hypertension and brachydactyly – that is, they have high blood pressure and short fingers. Unlike other people with long-standing hypertension, however, their hearts and kidneys are protected from the consequences of increased pressure in the blood vessels.
As Dr. Enno Klußmann, head of the "Anchored Signaling" research group at the Max Delbrück Center, and his team discovered a few years ago, this protection is thanks to an enzyme called phosphodiesterase 3A (PDE3A). "Due to a mutation, the enzyme molecules are more active than usual, probably because they are more likely to form pairs," explains Klußmann. The researcher now wants to mimic this effect using suitable compounds. His search for the ideal candidates will be supported by the Else Kröner-Fresenius Foundation for three years, starting in October, with €400,000.
Pairs probably work better
Around 1.3 billion people worldwide have high blood pressure, which, if left untreated, can lead to life-threatening heart damage, such as hypertrophy – an abnormally enlarged heart – and severe heart failure. "Such damage is not found in the hearts of people with HTNB or in animal models of HTNB," says Klußmann. His goal is to find compounds small enough to penetrate cells and mimic the protective effects of the PDE3A mutation. "These molecules could bind to the enzyme and initiate the formation of pairs," Klußmann explains.
The big search for these small molecules will begin at the Screening Unit of the Leibniz Research Institute for Molecular Pharmacology (FMP) on the Berlin-Buch campus. This unit, led by Dr. Jens Peter von Kries, has publicly accessible compound libraries containing around 170,000 such small molecules. Dr. Ester Paolocci, who recently completed her doctorate at the University of Oxford, will lead the project as a postdoc in Klußmann's research group.
Which compounds activate the enzyme?
"We are still very much in the dark when it comes to the search for candidates," says Klußmann. "We are approaching our experiments unbiased." This undertaking is being funded as one of the foundation's key projects, aiming to lead to new therapeutic approaches or change current textbook knowledge. Klußmann and his colleagues first plan to use FRET microscopy to identify which compounds might activate PDE3A. This method is a specialized form of fluorescence microscopy. The researchers will then further investigate the effects of the activators they identify. "We aim to demonstrate their anti-hypertrophic – ultimately heart-protective – effect in two different heart muscle models," explains Klußmann. The heart muscle cells will be obtained from rats and human induced pluripotent stem cells.
These findings would not automatically lead to a new medication, however. "General activation of PDE3A throughout the body is very likely to cause high blood pressure and significantly increase the risk of stroke," says Klußmann. "So, we first need to succeed in transporting the activating molecules specifically to those places in the body where they can exert their organ-protective effect." Possible outcomes could include drugs that prevent or alleviate heart damage in hypertensive patients or further developments that protect against hypertension-related kidney disease. Klußmann is confident: "Millions of people in this country alone would benefit from such interventions."
Text: Anke Brodmerkel
Further information
