Novel approaches to understanding EETs and cardiovascular disease

Some products of arachidonic acid have already been well studied: the prostanoids formed by cyclooxygenases are central mediators of inflammation, fever, and pain. Their synthesis is inhibited by drugs such as acetylsalicylic acid (aspirin). Likewise, the effects and mechanisms of leukotrienes, which are formed by lipoxygenases from arachidonic acid and serve as targets for asthma medications, are well known.

Less well understood, however, is a third group of lipids - the epoxyeicosatrienoic acids (EETs), which are produced from arachidonic acid by cytochrome P450 epoxygenases. It has been known for almost 40 years that EETs can trigger a range of beneficial biological effects: they lower blood pressure, have anti-inflammatory properties, and are neuroprotective. Yet even after decades of intensive research, the molecular pathways through which these effects are mediated remain unclear. As a result, no pharmacological targets are currently known that could be used to mimic the therapeutic potential of EETs.

A new research project funded by the German Research Foundation (DFG) under its Koselleck Program - led by Prof. Eugen Proschak and Prof. Stefan Offermanns - aims to shed light on this question through novel experimental approaches. Evidence suggests that cell membrane receptors may be involved, which could be activated either directly by EETs or after their incorporation into membrane lipids. The project, titled "Identification of membrane targets for lipid species containing esterified EETs (ELS)", will systematically search for transmembrane proteins that bind to EETs and mediate their effects. In addition, the researchers will test the hypothesis that EETs act not as free lipids but in a more complex form - that is, after being integrated into more complex membrane lipids.

We know these effects exist, but we still don't understand how they come about. Yet to develop an entirely new class of drugs, we urgently need this basic knowledge."

Prof. Eugen Proschak

A particular focus will be on endothelial cells - structures of the vascular system - and thus on diseases of the cardiovascular system.

The project brings together two research groups with complementary expertise: Prof. Proschak's group at the Institute of Pharmaceutical Chemistry, specializing in medicinal chemistry and the synthesis of pharmacological tools, and Prof. Offermanns' group at the Institute of Molecular Medicine, which uses classical and molecular pharmacological methods both in vitro and in vivo. Prof. Offermanns is also Director of the Max Planck Institute for Heart and Lung Research in Bad Nauheim.

Divided into four subprojects, the research combines chemical, pharmacological, and proteomic approaches - the latter encompassing the entirety of proteins present in a cell. With this innovative concept, the researchers hope to uncover the molecular mechanisms through which EETs exert their biological effects. A total of €1.25 million is available for this work until 2030.

Established in 2008, the Koselleck Program is named after Reinhart Koselleck (1923-2006), one of Germany's most important 20th-century historians and a co-founder of modern social history. Koselleck projects are awarded to "researchers distinguished by outstanding scientific achievements." Funding is reserved for particularly innovative and high-risk research approaches.

The project by Eugen Proschak and Stefan Offermanns exemplifies these criteria in an exceptional way: until now, all attempts to elucidate EETs' mechanism of action have failed. If this endeavor succeeds, the resulting insights could be groundbreaking - not least for the potential development of entirely new classes of drugs that specifically mimic the beneficial effects of EETs.