Long non-coding RNAs (lncRNAs) possess key regulatory functions within mammalian genomes. They can directly interact and mediate expression and functionality of proteins, other RNAs, as well as DNA. However, their contribution to the development and progression of cardiovascular disease remains largely elusive.
In this current study from the DZHK partner site Munich, the authors were able to identify the lncRNA MIAT as a crucial regulator of smooth muscle cell proliferation, migration, and trans-differentiation (into macrophage-like cells) through interaction with the transcription factors EGR1, ELK1, and KLF4. In lesional macrophages, MIAT further promoted translocation of NF-kB and thus inflammatory activity during plaque progression.
MIAT was identified in two independent human cohorts (Munich Vascular Biobank and Biobank of Karolinska Endarterectomies; BiKE) of carotid plaques and patients with - or at risk - of large artery stroke. Two independent murine models of plaque progression and destabilization in Miat-/- and ApoE-/-Miat-/- mice helped to further define the regulatory role of this specific lncRNA in vivo. The results were further validated in a preclinical model of advanced atherosclerosis in genetically mutated LDLR-/- Yucatan mini-pigs.