Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1

作者：Lemarie Catherine A; Shbat Layla; Marchesi Chiara; Angulo Orlando J; Deschenes Marie Eve; Blostein Mark D; Paradis Pierre; Schiffrin Ernesto L^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2011, 300(3): H745-H753.

DOI：10.1152/ajpheart.00321.2010

• homocysteine
• methylenetetrahydrofolate reductase
• endothelium
• telomeres

Lemarie CA, Shbat L, Marchesi C, Angulo OJ, Deschenes ME, Blostein MD, Paradis P, Schiffrin EL. Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1. Am J Physiol Heart Circ Physiol 300: H745-H753, 2011. First published December 17, 2010; doi:10.1152/ajpheart.00321.2010.-Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction in part as a result of enhanced oxidative stress. Function and survival of endothelial progenitor cells (EPCs, defined as sca1(+) c-kit(+) flk-1(+) bone marrow-derived cells), which significantly contribute to neovascularization and endothelial regeneration, depend on controlled production of reactive oxygen species (ROS). Mice heterozygous for the gene deletion of methylenetetrahydrofolate reductase (Mthfr(+/-)) have a 1.5- to 2-fold elevation in plasma homocysteine. This mild HHcy significantly reduced the number of circulating EPCs as well as their differentiation. Mthfr deficiency was also associated with increased ROS production and reduced nitric oxide (NO) generation in Mthfr(+/-) EPCs. Treatment of EPCs with sepiapterin, a precursor of tetrahydrobiopterin (BH(4)), a cofactor of endothelial nitric oxide synthase (eNOS), significantly reduced ROS and improved NO production. mRNA and protein expression of eNOS and the relative amount of eNOS dimer compared with monomer were decreased by Mthfr deficiency. Impaired differentiation of EPCs induced by Mthfr deficiency correlated with increased senescence, decreased telomere length, and reduced expression of SIRT1. Addition of sepiapterin maintained cell senescence and SIRT1 expression at levels comparable to the wild type. Taken together, these results demonstrate that Mthfr deficiency impairs EPC formation and increases EPC senescence by eNOS uncoupling and downregulation of SIRT1.

• 出版日期2011-3
• 单位河北医科大学