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July 2020

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Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis. Science Translational Medicine (2020), DZHK authors: D. Santovito, L. Natarelli, M. Aslani, E. Lutgens, P. von Hundelshausen, S. Steffens, J. Duchene, R.T.A. Megens, C. Weber

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 Atherosclerosis underlies the development of cardio- and cerebrovascular diseases which represent the main cause of death worldwide. The condition occurs overwhelmingly at bifurcations of the arterial tree, where the turbulence of blood flow promotes damage to the endothelial cells that line the vessels, favoring the recruitment of inflammatory cells and the eventual development of atherosclerotic plaques.

Endothelial cells express particularly high concentrations of miR-126-5p to protect them from damage. DZHK scientists from the Institute for Cardiovascular Prevention (IPEK) at the LMU Medical Center have now described an extraordinary mode of action of the molecule. miR-126-5p can unexpectedly be transferred into the nucleus of endothelial cells and, by simply interacting with it, suppresses the activity of the enzyme caspase-3, which is responsible for apoptosis. In this way, the molecule protects vascular integrity and reduces the extent of atherosclerotic lesions.

The multi-step process in the endothelial cells is triggered by high shear stress, which results in the formation of a molecular complex between miR-126-5p and an RNA-binding protein.

Once inside the nucleus, miR-126-5p is released from the complex and binds to an enzyme called caspase-3, thus inhibiting its activity. Caspase-3 itself is a crucial mediator of programmed cell death (apoptosis).

This hitherto unknown function of miR-126-5p represents a new principle of biological regulation. Together with an interdisciplinary network of international collaborators and within the framework of the Transregio-SFB TR267 and the SFB 1123, the team plans to investigate whether other miRNAs can also act in a similar or related way. In addition, further insights into the mechanisms that modulate the action of this signaling pathway might well open up new options for the treatment of vascular diseases.