Mycophenolic acid induces senescence of vascular precursor cells

Abstract

ObjectiveEndothelial dysfunction is central to the pathogenesis of many rheumatic diseases, typified by vascular inflammation and damage. Immunosuppressive drugs induce disease remission and lead to improved patient survival. However, there remains a higher incidence of cardiovascular disease in these patients even after adequate disease control. The purpose of this study was to determine the effect of mycophenolic acid (MPA), a commonly used immunosuppressive drug in rheumatology, on blood vessel or circulating endothelial colony forming cell number and function.MethodsWe tested whether mycophenolic acid exerts an inhibitory effect on proliferation, clonogenic potential and vasculogenic function of endothelial colony forming cell. We also studied potential mechanisms involved in the observed effects.ResultsTreatment with MPA decreased endothelial colony forming cell proliferation, clonogenic potential and vasculogenic function in a dose-dependent fashion. MPA increased senescence-associated β-galactosidase expression, p21 gene expression and p53 phosphorylation, indicative of activation of cellular senescence. Exogenous guanosine supplementation rescued diminished endothelial colony forming cell proliferation and indices of senescence, consistent with the known mechanism of action of MPA.ConclusionOur findings show that clinically relevant doses of MPA have potent anti-angiogenic and pro-senescent effects on vascular precursor cells in vitro, thus indicating that treatment with MPA can potentially affect vascular repair and regeneration. This warrants further studies in vivo to determine how MPA therapy contributes to vascular dysfunction and increased cardiovascular disease seen in patients with inflammatory rheumatic disease.

Premature senescence of placental decidua cells as a possible cause of miscarriage produced by mycophenolic acid

“…Senescence is the state of irreversible cell-cycle arrest, which is part of the normal cellular aging process and a response to a variety of stresses. MPA induce senescence in chronic myeloid leukemia cell lines [ 56 ], vascular precursor cells [ 37 ], and DMSC, as we reported here. The role of senescence as a general response to physiologic stress seems increasingly important.…”

“…The activation of the G2 checkpoint provides an opportunity for DNA repair. MPA treatment causes cell cycle arrest in G0/G1 in lymphocytes and vascular precursor cells [ 37 ]. The arrest of the cell cycle after DNA damage can also be induced at S or G2 phases, depending on the cell type, its active checkpoint mechanism, as well as its growth conditions [ 38 ].…”

“…Our results show that MPA induced a robust increase in the p21 protein levels in DMSC. Increased p21 protein by MPA treatment resulting in cell cycle arrest has been reported in insulin-secreting cells [ 49 ] and in vascular precursor cells [ 37 ]. According to these reports, it is feasible to suggest that the tandem p53/p21 is the MPA mediator of cell cycle arrest in DMSC.…”

Asymmetric inheritance of cytoophidia could contribute to determine cell fate and plasticity

“…[14] Additionally, IMPDH inhibitors can cause the appearance of senescence markers. [15] Whether lowering pyrimidine ribonucleotide pools also triggers the onset of premature senescence is not clear in the literature. Nevertheless, recent evidence suggests that CTPS blockage could turn on a senescence-like program by triggering profound changes in cell-cycle progression.…”

Reply:

“…In addition to the paper cited in our article, a recent publication by Go et al demonstrated a crucial role for mycophenolic acid in the senescence of endothelial cells and endothelial dysfunction. ( 4 )…”