IP: Dr. Vicente Andrés García

Resumen del proyecto: This project is framed in the context of the broad interest of our laboratory to investigate the molecular ana cellular mechanisms responsible of cardiovascular disease and premature and physiological aging. Cardiovascular disease (CVD) is the number one killer in developed countries and by 2020 is expected to be the main cause of morbi-mortality worldwide. This is due in part to progressive societal aging, which is one of the most salient demographic phenomena of our times and has a high medical and socioeconomic impact. A-type lamins (lamin A and C encoded by LMNA gene) are key regulators of nuclear structure and cell functions, as DNA transcription and replication, DNA damage repaired response, or mechano-sensing and signal transduction. In addition, LMNA mutations provoke several human diseases termed laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS), a rare disease caused by accumulation of the mutant lamin A protein called progerin. HGPS is a premature aging disease characterized among other signs by excessive atherosclerosis and death of patients in adolescence mainly from myocardial infarction or stroke. Progerin has also been detected at low level in aged non-HGPS individuals, suggesting a potential role for progerin in normal aging. Our group has made seminal contributions over the last decade to understanding the role of A-type lamins in different physio-pathological processes. We have recently started studies on the role of A-type lamins expression in immune cells in atherosclerosis development and aging. Using transgenic mouse models, we have demonstrated increased atherosclerosis development when lamin A/C is missing in hematopoietic precursors. However, the aggravation of atherosclerosis in the absence of lamin A/C is not due to changes in the number of circulating leukocytes or in the adherence of monocytes and neutrophils to the inflamed vessel wall, but is associated with increased leukocyte extravasation and reduced migration velocity after extravasation. In a complementary pilot study with peripheral blood mononuclear cells (PBMCs) from wild-type mice ranging from 3 to 102 weeks of age, we found lower levels of lamin A/C in neutrophils and Ly6CLow patrolling monocytes isolated from old versus young mice; by analysing PBMCs from age-matched men and women ranging 20 to 40 years of age, we also found higher level of lamin A/C protein in B-lymphocytes and classical and non-classical monocytes of women versus men (age range when women show normal hormonal activity). Based on these preliminary results, we propose the following working hypothesis: 1) lamin A/C expression in PBMCs protects from atherosclerosis development; 2) the down-regulation of lamin A/C in murine leukocytes from old mice might represent a novel mechanism contributing to age-dependent atherosclerosis development; 3) hormonal factors in young women may help to maintain higher levels of lamin A/C in some subpopulations of PBMCs compared with age-matched men, and thus contribute to cardiovascular protection in premenopausal women. In the present project we propose to investigate the levels of expression of lamin A/C in different populations of PBMCs from age-matched men and women ranging from young to old age. This investigation should improve our knowledge on the role of A-type lamins in monocyte effector differentiation/function and atherosclerosis (AIM 1), identify new mechanisms underlying age- and gender-dependent regulation of A-type lamins expression (AIM 2), and assess the contribution of progerin to physiological aging and to age-dependent atherosclerosis development (AIM 3).

Entidad financiadora: Ministerio de Ciencia e Innovación, Programa Estatal de I+D+i