Portland Press, Clinical Science, 12(129), p. 1061-1075, 2015
DOI: 10.1042/cs20140753
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AIMS Reduced nitric oxide – cyclic guanosine monophosphate (cGMP) signaling is observed in age-related vascular disease. We hypothesize that this disturbed signaling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMC), and that the underlying mechanism plays a role in human age-related vascular disease. In previous studies in mice with increased genomic instability due to DNA repair defects we discovered that decreased cGMP levels due to PDE overactivity in VSMC is a candidate mechanism. Also, increased VSMC senescence was observed. Human VSMCs were obtained from normal medial aortic explants from 5 donors (20-54 years old). Serial passaging until senescence was performed and RNA was isolated from the 5 independent cultures at different passages to quantify expression of the PDE 1A, PDE1C and PDE 5 genes. Real-time qPCR was performed. Ct values of PDE subspecies were corrected for reference gene TBP. All data are expressed relative to the lowest passage, which was set at 1. WB was performed to ascertain the validity of qPCR data. We also searched for SNPs inside the PDE genes in the publicly available GWAS meta-analysis results for BP, PP, PWV and cIMT. A p-value of <2.87x10^-4 after applying Bonferroni correction for multiple testing (0.05/174) was considered significant. METHODS In vitro VSMC senescence lead to increased PDE1, which might lead to decreased cGMP signaling. PDE1A gene variations are associated with increased diastolic blood pressure and carotid intima media thickness. These results suggest that PDE1 plays a pivotal role in human age-related vascular disease, implicating senescent VSMC. To investigate the effect of cell senescence on PDE1A, PDE1C and PDE5, in human VSMC. To investigate if SNPs in the PDE genes are associated with blood pressure (BP), Pulse pressure (PP), pulse wave velocity (PWV) and carotid intima media thickness (cIMT) in a candidate gene association study.