Dr.in Selma Osmanagic-Myers
MedUni Wien RESEARCHER OF THE MONTH March 2020
Blood vessel aging and cardiovascular disease
In modern societies with increasingly older populations, age is becoming a major risk factor for cardiovascular disease (CVD). However, the underlying molecular mechanisms especially with regard to aging of the innermost blood vessel layer, the endothelium, are still poorly understood. In the current study, we examined age-related changes in the endothelium using endothelium-specific mouse model system of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS)1. HGPS, caused by a mutation in the Lamin A gene, leads to CVD and premature death from heart failure at teenage age2-4. We could show for the first time that many aspects of cardiovascular pathology in HGPS patients also occurred in endothelium-specific HGPS mice demonstrating a direct correlation between endothelial aging and CVD. At the molecular level, HGPS endothelial cells showed impaired response to flow shear stress and activated proatherogenic and profibrotic MRTFA (Myocardin Transcription Factor A) signaling. Importantly, by inhibiting MRTFA, we were able to rescue the profibrotic phenotype. Altogether, this study provides novel insights into the molecular processes that lead to aging of blood vessels paving ground for development of new beneficial therapies for CVD in HGPS- and geriatric patients.
- Osmanagic-Myers, S. et al. Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse. J Clin Invest 129, 531-545, doi:10.1172/JCI121297 (2019).
- Gordon, L. B., Rothman, F. G., Lopez-Otin, C. & Misteli, T. Progeria: a paradigm for translational medicine. Cell 156, 400-407, doi:10.1016/j.cell.2013.12.028 (2014).
- Osmanagic-Myers, S., Dechat, T. & Foisner, R. Lamins at the crossroads of mechanosignaling. Genes Dev 29, 225-237, doi:10.1101/gad.255968.114 (2015).
- Vidak, S. & Foisner, R. Molecular insights into the premature aging disease progeria. Histochemistry and cell biology 145, 401-417, doi:10.1007/s00418-016-1411-1 (2016).