Abstract-Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. (VSMCs), and intracellular and extracellular lipids. Plaque disruption results in acute myocardial infarction and stroke, whereas repeated rounds of subclinical rupture and repair also promote plaque growth. Although VSMC proliferation occurs in atherogenesis, most proliferating cells are macrophages, and VSMC mitotic rates are lower in advanced plaques than early lesions, even after plaque rupture, 1 suggesting that plaque VSMCs may exhibit senescence.Cellular senescence can be defined as cell cycle arrest accompanying the exhaustion of replicative potential. 2 Senescent cells display a characteristic morphology (vacuolated, flattened cells) and gene expression, including markers such as senescence-associated ␤-galactosidase (SA␤G). 3 Senescence may be triggered by 2 broadly different mechanisms. In most primary cells, the telomeres of chromosomes shorten at each cell division because of incomplete chromosomal replication. Replicative senescence may be induced at critical telomere lengths or structures, such as telomeric fusion or dicentrics or loss of telomere-bound factors. 4,5 Cells also undergo "stress-induced premature senescence" (SIPS), for example, in response to activated oncogenes (eg, Ha-Ras) and suboptimal culture conditions. 6 Although telomere loss occurs with replication, both premature senescence and telomere breaks may be induced by oxidative DNA damage. Reactive oxygen species (ROS), particularly superoxide anions, hydrogen peroxide, and hydroxyl radicals, can produce a large variety of DNA damage, including DNA strand breaks and DNA base modifications. ROS can accelerate telomere loss during replication in some cell types 7 but also induces premature senescence independently of telomere shortening. 8 Increased levels of ROS are Original

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The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.

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We study an on-line problem that is motivated by the networking problem of dynamically adjusting delays of acknowledgments in the Transmission Control Protocol (TCP). We provide a theoretical model for this problem in which the goal is to send acks at times that minimize a linear combination of the cost for the number of acknowledgments sent and the cost for the additional latency introduced by delaying acknowledgments. To study the usefulness of applying packet arrival time prediction to this problem, we assume there is an oracle that provides the algorithm with the times of the next L arrivals, for some L Ն 0.We give two different objective functions for measuring the cost of a solution, each with its own measure of latency cost. For each objective function we first give an O(n 2 )-time dynamic programming algorithm for optimally solving the off-line problem. Then we describe an on-line algorithm that greedily acknowledges exactly when the cost for an acknowledgment is less than the latency cost incurred by not acknowledging. We show that for this algorithm there is a sequence of n packet arrivals for which it is ⍀ ( ͌ n)-competitive for the first objective function, 2-competitive for the second function for L ϭ 0, and 1-competitive for the second function for L ϭ 1. Next we present a second on-line algorithm which is a slight modification of the first, and we prove that it is 2-competitive for both objective functions for all L. We also give lower bounds on the competitive ratio for any deterministic on-line algorithm. These results show that for each objective function, at least one of our algorithms is optimal.Finally, we give some initial empirical results using arrival sequences from real network traffic where we compare the two methods used in TCP for acknowledgment delay with our two on-line algorithms. In all cases we examine performance with L ϭ 0 and L ϭ 1.

MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) are tightly regulated enzymes that coordinate matrix production and degradation. The obvious need for a dynamic process that regulates collagen turnover is evident in wound repair and remodeling (2,3). However, MMPs and TIMPs are involved in other significant but less obvious processes, such as tumor invasion and metastasis (4 -7), inflammatory responses (8), embryonic development (9,10), arthritic diseases (11,12), and multiple sclerosis (13,14).Recently, Herren et al. (15) discovered that certain metalloproteinases play a role in apoptosis. In particular, MMPs play a role in caspase activation by processing membrane-bound ␤-catenin to its active form via proteolysis. MMPs may also be involved in processing the transmembrane Fas ligand to the soluble Fas ligand (16). In addition, MMPs convert the membrane-bound form of protumor necrosis factor (TNF)-␣ to the mature active inflammatory cytokine through proteolytic cleavage of a critical alanine-valine bond at amino acids 76 and 77 (17,18).Alternatively, TIMP-1 overexpression prevented programmed cell death in a Burkitt's lymphoma cell line through both CD-95 (Fas)-dependent and -independent pathways. TIMP-1 overexpression upregulated Bcl-xL and decreased nuclear factor (NF)-B activity, and the protective effect was not related to metalloproteinase inhibition (19). Furthermore, TIMP-1 expression has been used to prevent apoptotic cell death induced by hydrogen peroxide, adriamycin, and X-ray irradiation in human breast epithelial cell lines (20).Pancreatic ␤-cells and islets are particularly sensitive to cytokine-mediated damage. Cytokine-treated rodent (and human) pancreatic islets demonstrate increased expression of the inducible nitric oxide synthase (iNOS) gene that in turn leads to nitric oxide (NO) production (21). NO inhibits glucose-stimulated insulin secretion (GSIS) and induces ␤-cell damage. Whereas inhibitors of iNOS, such as N-monomethyl-L arginine and L-N-arginine-methylester, can partially prevent cytokine-mediated ␤-cell damage through inhibition of NO production; NO-independent From the Leslie and Susan Gonda

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