No abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E‐deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC‐specific progerin expression. This stress pathway was also activated in HGPS patient‐derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC‐specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging‐dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.

Abstract Vast parts of mammalian genomes are actively transcribed, predominantely giving rise to non-coding RNA transcripts including microRNAs, long non-coding RNA and circular RNAs amongst others. Contrary to previous opinions that most of these RNA are non-functional molecules, they are now recognised as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional non-coding RNAs has opened up new research avenues aiming at understanding non-coding RNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review we give an update on the current progress in non-coding RNA research, particularly focussing on cardiovascular physiological and disease processes, which are subject of current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of non-coding RNAs in the cardiovascular system.