Abstract
Stress-induced premature cellular senescence is a significant factor in the onset of age-dependent disease in the cardiovascular system. Plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1/p53 target gene and negative regulator of the plasmin-based pericellular proteolytic cascade, is elevated in arterial plaques, vessel fibrosis, arteriosclerosis, and thrombosis, correlating with increased tissue TGF-β1 levels. Additionally, PAI-1 is necessary and sufficient for the induction of p53-dependent replicative senescence. The mechanism of PAI-1 transcription in senescent cells appears to be dependent on caveolin-1 signaling. Src kinases are upstream effectors of both FAK and caveolin-1 activation as FAKY577,Y861 and caveolin-1Y14 phosphorylation are not detected in TGF-β1-stimulated src family kinase (pp60c-src, Yes, Fyn) triple-deficient (SYF−/−/−) cells. However, restoration of pp60c-src expression in SYF-null cells rescued both caveolin-1Y14 phosphorylation and PAI-1 induction in response to TGF-β1. Furthermore, TGF-β1-initiated Src phosphorylation of caveolin-1Y14 is critical in Rho-ROCK-mediated suppression of the SMAD phosphatase PPM1A maintaining and, accordingly, SMAD2/3-dependent transcription of the PAI-1 gene. Importantly, TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells, correlating with reductions in both Rho-GTP loading and SMAD2/3 phosphorylation. These findings implicate caveolin-1 in expression controls on specific TGF-β1/p53 responsive growth arrest genes. Indeed, up-regulation of caveolin-1 appears to stall cells in G0/G1 via activation of the p53/p21 cell cycle arrest pathway and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene. Although the mechanism is unclear, caveolin-1 inhibits p53/MDM2 complex formation resulting in p53 stabilization, induction of p53-target cell cycle arrest genes (including PAI-1), and entrance into premature senescence while stimulating the ATM→p53→p21 pathway. Identification of molecular events underlying senescence-associated PAI-1 expression in response to TGF-β1/src kinase/p53 signaling may provide novel targets for the therapy of cardiovascular disease.
Highlights
Vascular smooth muscle cell (VSMC) Senescence and Vascular DiseaseTissue-resident cells acquire the morphologic and biochemical hallmarks of a senescent phenotype during development of several age-related disorders including atherosclerosis, idiopathic lung fibrosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer’s and Parkinson’s disease, cancer, and renal fibrosis [1,2,3,4]
The mechanism is unclear, caveolin-1 inhibits p53/mouse double minute 2 homolog (MDM2) complex formation resulting in p53 stabilization, induction of p53-target cell cycle arrest genes, and entrance into premature senescence while stimulating the ATM→p53→p21 pathway
TGF-β1 activates p53 and both caveolin-1 and p53 are required for expression of the profibrotic p53 target Plasminogen activator inhibitor-1 (PAI-1) gene and VSMC senescence [51,59]; there are considerable cell type-dependent controls on the specific involvement of caveolin-1 in growth regulation, entry into a senescent state, and transcription of cell cycle arrest genes
Summary
Tissue-resident cells acquire the morphologic and biochemical hallmarks of a senescent phenotype during development of several age-related disorders including atherosclerosis, idiopathic lung fibrosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer’s and Parkinson’s disease, cancer, and renal fibrosis [1,2,3,4]. Accelerated VSMC aging in atherosclerosis results from replicative stress (i.e., reduced telomere integrity) or premature senescence due to elevated levels of ROS and DNA damage [5,14]. Plaque-associated VSMCs exhibit other molecular traits characteristic of the senescent state including induction of the cell cycle inhibitors p16 and p21, reduced E2F transcriptional activation of proliferation-promoting genes due to retinoblastoma (Rb) protein hypophosphorylation and up-regulation of p53 [14,15,16,22]. P53 activation sensitizes VSMCs to Fas-mediated apoptosis by increasing cell surface Fas levels This has significant consequences; unlike viable VSMCs which promote plaque stability via maintenance of collagen expression, a major determinant of the fibrous cap tensile strength perhaps in response to elevations in vessel TGF-β levels, apoptotic VSMCs contribute to plaque vulnerability while simultaneously functioning as nucleating structures for vascular calcification [14]. Senescent VSMCs overexpress osteoblastic genes (e.g., alkaline phosphatase, RUNX-2, type I collagen, BMP-2) suggesting that acquisition of a pro-calcificatory phenotype is one aspect of a cell type-exclusive senescence program in the vascular system [24,25]
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