Invited commentary

Abstract

Cellular senescence is an important contributor to the development of atherosclerosis. The mechanisms by which senescence promotes atherosclerosis, however, remain poorly understood. This important study by Lv et al demonstrates the causal association between reduced expression of peptidyl-prolyl cis/trans isomerase (Pin 1), increased vascular smooth muscle cell (VSMC) senescence, increased cellular senescence molecules p21 and p53, and reduced cell cycle-related cyclin-dependent kinases based on gain- and loss-of-function studies performed in vitro. In subsequent experiments, inhibition of Pin 1 was found to exacerbate experimental atherosclerosis. Thus, the authors postulate that Pin 1, likely acting upstream of the cellular senescence cascade, limits atherosclerosis by limiting VSMC senescence. An unexpected finding was that manipulation of the Pin 1 gene in vitro altered the expression of messenger RNA for p21, p53, p65, Gadd45, and cyclin-dependent kinases. These modulations are not attributable to variation in Pin 1 isomerase activity per se, leaving open the question of exactly which Pin 1-mediated actions suppress VSMC senescence. Senescent VSMCs express high levels of proatherogenic secretory molecules, which promote cell migration, extracellular matrix degradation, and the formation and activity of the inflammasome.1Gardner S.E. Humphry M. Bennett M.R. Clarke M.C. Senescent vascular smooth muscle cells drive inflammation through an interleukin-1alpha-dependent senescence-associated secretory phenotype.Arterioscl Thromb Vasc Biol. 2015; 35: 1963-1974Crossref PubMed Scopus (164) Google Scholar Further experiments should investigate how Pin 1 affects the VSMC senescence-associated secretory phenotype. In addition to senescent VSMCs, senescent foam cells are potent promoters of atherogenesis.2Childs B.G. Baker D.J. Wijshake T. Conover C.A. Campisi J. van Deursen J.M. Senescent intimal foam cells are deleterious at all stages of atherosclerosis.Science. 2016; 354: 472-477Crossref PubMed Scopus (605) Google Scholar This raises possibility that senescent foam cells may contribute to Pin 1 inhibition-mediated atherosclerosis. Thus, further experiments should be performed using VSMC- or myeloid cell-specific Pin 1-deficient mice to clarify the relative contributions of VSMC- and macrophage-derived Pin 1 to atherogenesis. The potential influence of Pin 1 on autophagy should also be investigated, given the causal association between defective autophagy and atherosclerosis.3Grootaert M.O. da Costa Martins P.A. Bitsch N. Pintelon I. De Meyer G.R. Martinet W. et al.Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis.Autophagy. 2015; 11: 2014-2032Crossref PubMed Scopus (178) Google Scholar Several polymorphisms in the gene encoding for Pin 1 are associated with a reduced risk for various cancers.4Xu H.R. Xu Z.F. Sun Y.L. Han J.J. Li Z.J. The -842G/C polymorphisms of PIN1 contributes to cancer risk: a meta-analysis of 10 case-control studies.PLoS One. 2013; 8: e71516Crossref PubMed Scopus (3) Google Scholar These or other known Pin 1 variants should be investigated to shed more light on the heritable susceptibility for atherosclerosis. Also, do hyperlipidemia and diabetes, two major atherosclerotic risk factors, influence Pin 1 expression? In a previous study,5Paneni F. Costantino S. Castello L. Battista R. Capretti G. Chiandotto S. et al.Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes.Eur Heart J. 2015; 36: 817-828Crossref PubMed Scopus (71) Google Scholar circulating monocytes harvested from diabetic patients demonstrate increased Pin 1 expression, and hyperglycemia has been found to upregulate expression in human endothelial cells in vitro. This study adds to the growing body of knowledge regarding the role of Pin 1 function in the regulation of atherosclerosis. Systemic augmentation of Pin 1 will isomerize phosphorylated serine/threonine-proline motif-containing proteins throughout the body, limiting clinical applicability due to undesirable off-target effects. And to date, no Pin 1 agonists or activators have been developed for clinical applications. Overcoming these obstacles will be necessary for the successful clinical translation of Pin 1-mediated therapeutic interventions in the treatment of atherosclerotic diseases. Downregulation of Pin1 in human atherosclerosis and its association with vascular smooth muscle cell senescenceJournal of Vascular SurgeryVol. 68Issue 3PreviewPin1 is prevalently overexpressed in human cancers and implicated to regulate cell growth and apoptosis. Thus far, however, no role for Pin1 has been described in modulating vascular smooth muscle cell (VSMC) senescence. Full-Text PDF Open Archive