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MHH researchers find novel regulatory RNA that controls inflammation and scarring of the heart muscle during repair processes.
More than 300,000 people suffer a heart attack in Germany every year. The heart muscle is then no longer supplied with sufficient blood and oxygen, and part of the tissue dies and scars. Unlike the liver, the heart of an adult human can hardly regenerate. However, it is capable of initiating limited repair processes. Macrophages play an important role in this process. These giant phagocytes of the innate immune system remove dead tissue and initiate the subsequent – albeit limited – self-healing process. However, the immune cells are ambivalent and can also trigger negative processes that lead to chronic heart failure (cardiac insufficiency).
The so-called polarisation of macrophages is decisive for the positive or negative influence. In this reversible process, the immune cells either react as M1 macrophages, promoting inflammation, or as M2 macrophages, resolving inflammation and supporting tissue repair. A team led by Prof. Dr. Dr. Thomas Thum, head of the Institute for Molecular and Translational Therapy Strategies at Hannover Medical School (MHH), has now discovered an important molecular switch for macrophage polarisation. This could open up a completely new therapeutic approach for the treatment of heart attacks and heart failure. The results have been published in the renowned European Heart Journal.
circHIPK2 regulates macrophage polarisation
In their study, the researchers discovered circHIPK2, a novel circular RNA (circRNA) that was found to be increased in inflammatory M1 macrophages after a heart attack. Circular RNAs belong to the non-coding RNAs (ncRNA) family and, unlike messenger RNA (mRNA), do not function as a blueprint for protein production and therefore do not translate genetic information. Instead, they regulate many processes within cells. Within the ncRNA family, circRNAs are particularly stable and species-conserved, meaning they have remained largely unchanged over the course of evolution. This makes them ideal target structures for drugs.
‘We have identified circHIPK2 as an important regulator of macrophage polarisation after a heart attack,’ explains Professor Thum. ‘As a molecular switch, circHIPK2 promotes the formation of so-called stress granules in macrophages.’ This triggers an inflammatory cascade. After activation, the immune cells release pro-inflammatory messenger substances, thereby directly contributing to fibrosis. In the process, the heart muscle tissue in the infarct region deposits more connective tissue, leading to scarring and stiffening. Fibrosis prevents the heart muscle from working properly, which can lead to heart failure.
Targeted elimination improves cardiac performance
The researchers investigated the newly discovered circHIPK2 in various systems, including directly in human heart tissue. In model systems, they were able to show how the inhibition of circHIPK2 in macrophages affects existing heart failure. Heart function was assessed using cardiac ultrasound and positron emission tomography (PET) imaging, among other methods. PET scans are used to visualise molecular processes in the body. ‘The targeted elimination of circHIPK2 in macrophages reduced inflammatory reactions, slowed down scarring of the heart muscle and significantly improved cardiac performance,’ Professor Thum notes.
Test model ‘living heart sections’
This protective effect was also observed in human tissue. To investigate this, the researchers used induced pluripotent stem cells (IPSCs). These are genetically reprogrammed body cells that have similar properties to embryonic stem cells, meaning they can develop into all types of tissue – in this case, macrophages. What makes them special is that the pro-inflammatory molecular switch circHIPK2 has been deactivated in them. ‘We tested the circHIPK2-modulated human macrophages in heart tissue from patients with heart failure,’ says the cardiologist. To do this, the researchers used the ‘living heart slice’ method. The material for this comes from the MHH Department for Cardiac, Thoracic, Transplant and Vascular Surgery and is, so to speak, tissue waste from hearts that no longer function, which were removed during transplantation. These heart muscle slices continue to live and beat in nutrient solution for many days or even weeks.
New therapeutic approach
‘This unique platform enabled us to translate molecular insights into a clinically meaningful context – and to show that silencing circHIPK2 promotes cardiac healing and reduces inflammatory damage,’ emphasises Professor Thum. The targeted treatment of immune cells – especially macrophages – with RNA-based therapies could open up a completely new treatment approach for heart attacks and heart failure.
The work was carried out in collaboration between the Institute for Molecular and Translational Therapy Strategies and the MHH clinics for cardiology and angiology, paediatric pneumology, allergology and neonatology, nuclear medicine, the Department of Molecular and Translational Cardiology and the Centre for Translational Regenerative Medicine at the MHH.
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Further information is available from Prof. Dr Dr Thomas Thum, thum.thomas@mh-hannover.de.
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaf111...
Prof. Dr. Dr. Thomas Thum has investigated a new RNA therapy for heart attacks using living heart se ...
Copyright: Karin Kaiser/MHH.
Living heart sections enable testing on human tissue for the new RNA therapy.
Copyright: Karin Kaiser/MHH.
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