Mecanismos moleculares y celulares implicados en el síndrome de progeria de Hutchinson-Gilford y potenciales terapias

Laburpena

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by a mutation in the LMNA gene that leads to the production of an anomalous protein called progerin. Premature aging and the associated cardiovascular disease are the main features of this pathology. Life expectancy of HGPS patients is reduced to 14.6 years on average, and the main cause of death is myocardial infarction or stroke provoked by accelerated atherosclerosis. Considering the low number of patients and low sample availability, it is essential to develop animal models that recapitulate human pathology. In this Doctoral Thesis, we have generated a new atheroprone mouse model of HGPS, Ldlr−/− LmnaG609G/G609G, that mimics most of its clinical symptoms, including accelerated atherosclerosis and premature aging. This new HGPS mouse model is a potentially useful tool for progeria studies. In this Doctoral Thesis, we also investigated novel mechanisms involved in cardiovascular disease in HGPS and designed different therapies to improve survival and quality of life. First, a high-throughput analysis of differentially-expressed microRNAs and its integration with the analysis of altered messenger RNAs in cardiac tissue of Apoe−/− LmnaG609G/G609G mice, led us to perform an in vivo treatment with antagomiR-340-5p (miR-340-5p inhibitor). This treatment resulted in a modest improvement in survival, without reversion of the cardiac phenotype. Next, during an analysis of molecular and cellular mechanisms involved in accelerated atherosclerosis in HGPS, we observed signs of endothelial-to-mesenchymal transition (endMT) mediated by TGFβ signaling in mouse models with systemic progerin expression (Apoe−/− LmnaG609G/G609G and Ldlr−/− LmnaG609G/G609G) and with vascular smooth muscle cell (VSMC)-specific progerin expression (Apoe−/−LmnaLCS/LCS SM22αCre). These alterations were not observed in a model with progerin expression restricted to endothelial cells (Apoe−/− LmnaLCS/LCS Cdh5CreERT2), indicating that both accelerated atherosclerosis and endMT are caused by VSMC death induced by progerin expression. Pharmacological intervention with a TGFβ signaling inhibitor in Apoe−/− LmnaLCS/LCS SM22αCre mice reduced leukocyte recruitment, improved vascular phenotype in thoracic aorta and partially suppressed endMT. These findings identify TGFβ signaling and the endMT event as molecular mechanisms involved in accelerated atherosclerosis in HGPS and represent a new therapeutic target. In addition, the similarities between HGPS and physiological aging open the possibility to extrapolate these results to the general population