Gas6 delays senescence in vascular smooth muscle cells through the PI3K/ Akt/FoxO signaling pathway.

BACKGROUND/AIMS: Growth arrest-specific protein 6 (Gas6) is a cytokine that can be synthesized by a variety of cell types and secreted into the extracellular matrix. Previous studies have confirmed that Gas6 is involved in certain pathophysiological processes of the cardiovascular system through binding to its receptor, Axl. In the present study, we investigated the role of Gas6 in cellular senescence and explored the mechanisms underlying its activity. METHODS: We used vascular smooth muscle cells (VSMCs) to create two cellular senescence models, one for replicative senescence (RS) and one for induced senescence (IS), to test the hypothesis that Gas6 delays senescence. RESULTS: Gas6-treated cells appear relatively younger compared with non-Gas6-treated cells. In particular, Gas6-treated cells displayed decreased staining for SA-ß-Gal, fewer G1 phase cells, and decreased levels of p16(INK4a) and p21(Cip1) expression; conversely, Gas6-treated cells displayed more S phase cells and significantly increased proliferation indexes. Furthermore, in both the IS and RS models with Gas6 treatment, the levels of PI3K, p-Akt, and p-FoxO3a decreased following Axl inhibition by R428; similarly, the levels of p-Akt and p-FoxO3a also decreased following PI3K inhibition by LY294002. CONCLUSION: Gas6/Axl signaling is essential for delaying the cellular senescence process regulated by the PI3K/Akt/FoxO signaling pathway.

The impact of metabolic syndrome and hypertension on medical costs of patients with acute myocardial infarction at hospital.

OBJECTIVE: This study aimed to find out the impact of metabolic syndrome (MS) and hypertension on medical costs of patients with acute myocardial infarction (AMI) at hospital. METHODS: Patients with AMI at Qilu Hospital of Shandong University during January 2011 to May 2013 were separated into four groups according to whether with MS or history of hypertension. Comparison of medical costs, complication rate and cost-effectiveness ratio were analyzed. RESULTS: We found that total costs, each day costs, medical treatment costs, chemical examination costs and drug costs were significantly different in four groups. In variance analysis, MS led to high medical costs without significance. Hypertension was a significant factor influencing medical costs and lead to low medical costs. In multiple linear regression, we found that body mass index (BMI) and percutaneous coronary intervention (PCI) were important predictors of total costs and each day costs. With higher BMI and utilization rate of PCI, medical costs were increased. Trend of total costs in four groups is similar to that of the rate of PCI utilization. CONCLUSIONS: Metabolic syndrome has no impact on medical costs because of discordance in MS components. Hypertension will lead to lower PCI utilization rate, which results in less medical costs and bad hospital outcomes.

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway.

Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl- and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin II-induced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin II-induced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, Axl-Fc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy.

A medical costs study of older patients with acute myocardial infarction and metabolic syndrome in hospital.

BACKGROUND: Older patients with acute myocardial infarction (AMI) usually have a poor prognosis, but whether this poor prognosis leads to high hospital costs remains unclear. This study investigated the clinical outcomes of and costs incurred by older patients with AMI and metabolic syndrome (MS) in hospital. METHODS AND RESULTS: Patients with AMI seen at Qilu Hospital of Shandong University between January 2011 and May 2013 were separated into four groups: young non-MS patients (n=282), older non-MS patients (n=324), young MS patients (n=217), and older MS patients (n=174). We found that advanced age was significantly associated with worse clinical outcomes, and that the clinical outcomes in patients with AMI and MS are also worsened. At the same cost (RMB¥10,000), older patients with and without MS had a markedly increased number of cardiovascular incidences compared with younger patients without MS. In a comparison of the incremental cost-effectiveness ratio (ICER) of percutaneous coronary intervention, older patients without MS had a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with young patients without MS, but a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with older MS patients. CONCLUSION: Older AMI patients have poor clinical outcomes and their treatment is not cost-effective; however, the results are worse in patients with AMI and MS. Percutaneous coronary intervention is a cost-effective therapy in older patients with AMI, but its cost-effectiveness decreases in patients with AMI and MS.