Vascular Aging from DNA Damage to Protection
Aging is highly associated with development of cardiovascular disease; however, the underlying mechanisms of these processes are not well understood. Recent advancements in aging research underscore the importance of DNA damage and subsequent cellular senescence in the aging process. In our research we investigated the effect of impaired DNA repair on vascular function. We employed murine experimental models with impaired DNA repair, namely Ercc1d/- and XPDTTD progeroid mice. Both strains showed accelerated vascular aging, represented in increased vascular stiffness, higher blood pressure, cellular senescence and vasomotor dysfunction. Furthermore we found an association between variations in human DNA repair gene DDB2 and vascular stiffness in the population of AortaGen cohort. In addition, we looked at possible novel treatments for age-related cardiovascular disease. Putatively protective agents were investigated. Phosphodiesterase inhibitors vinpocetin and sildenafil improved vasodilator function in progeroid mice. Red wine extract MAS receptor agonist cyclic angiotensin-(1-7) prevented endothelial senescence induced by oxidative stress. The latter also exerted beneficial endothelial and cardiac effects in an animal model of myocardial infarction. Furthermore, the mechanism for vasorelaxations induced by the protective angiotensin II type 2 (AT2) receptor agonist Compound 21 were investigated, showing that modulation of Ca2+ effects is involved indepently from AT2 receptor activation. In summary, the instability of DNA plays an important role in the development of cardiovascular disease and agents affecting DNA stability or vasomotor signaling are promising agents for treatment and prevention of cardiovascular disease.
|Keywords||DNA repair, aging, cardiovascular disease, endothelium, genomic instability, renin angiotensin system, vascular smooth muscle|
|Promotor||Danser, A.H.J. (Jan)|
|Publisher||Erasmus MC: University Medical Center Rotterdam|
|Sponsor||Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged.|
Durik, M.. (2012, November). Vascular Aging from DNA Damage to Protection . Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/37745