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442. Sphingosine 1-phosphate inhibits angiogenesis in ex vivo human aortic valves.

Author

Mascall, K. S., Small, G., Gibson, G., and Nixon, G. F.

Subjects
*AORTIC stenosis, *CALCIFICATION, *HEART failure
Abstract

Aortic valve stenosis (AVS) is closely associated with increased valve inflammation leading to calcification and ultimately results in cardiac failure if untreated. Currently the only therapeutic option is surgical valve replacement. Recent studies have indicated that increased angiogenesis within the valve may facilitate access of inflammatory cells and this plays an important role in the pathogenesis of AVS. Preventing angiogenesis in aortic valves is therefore a novel therapeutic target in this disease. Sphingosine 1-phosphate(S1P) is a lipid mediator present in plasma and produces intracellular effects via specific S1P receptors. We have previously shown that S1P can inhibit angiogenesis in human arteries (Mascall et al, 2012). The aim of the current study was to determine the effect of S1P on angiogenesis in human aortic valves. Valves from patients undergoing valve replacement surgery for AVS (diseased) or aortic regurgitation (non-diseased) were cut 2mm² pieces and embedded in Matrigel. Valve pieces were incubated for up to 14 days in growth factor-supplemented medium and angiogenic sprouts were quantified. Sprouts consisting of endothelial cells (confirmed by uptake of acetylated-LDL) increased in number from day 5 until day 14 and this was significantly greater in diseased compared to non-diseased valves (number of sprouts observed at day 14, non-diseased 60 ± 8 versus diseased 110 ± 12, n=4 per group, mean ± s.e.m., ANOVA, p<0.05). Treatment of either diseased or non-diseased valve tissue with 1µM S1P resulted in a significant decrease in endothelial sprout formation compared to non-treated valves (number of sprouts observed at day 14, non-diseased valves-untreated 71 ± 5 versus S1P-treated 18 ± 3, n=3 per group; diseased valves -- untreated 116 ± 9 versus S1P-treated 38 ± 5, n=3 per group, p<0.05). To examine this further, we assessed the activity of matrix metalloprotineases (MMPs) which are associated with angiogenesis. Activity of MMP-2 was significantly greater in diseased compared to control valves as assessed by in vitro gelatinolytic activity. Incubation with 1µM S1P decreased MMP activity in diseased valves (gelatinolytic activity observed at day 14, 94 ± 11% decrease in untreated valves compared to treated, n=3 per group, p<0.05). To determine the potential mechanisms involved we examined expression of the angiostatic protein, soluble fms-like tyrosine kinase-1 (sflt-1). Immunoblotting of valve homogenates demonstrated that sflt-1 expression is significantly decreased in diseased valves compared to control valves. Homogenates from diseased valves incubated with 1µM S1P for 14 days had a significantly increased expression of sflt-1 (n=3 per group). In conclusion, S1P can inhibit angiogenesis in human aortic valves, possibly via increasing expression of the angiostatic protein sflt-1. This mechanism may provide a therapeutic target in AVS. [ABSTRACT FROM AUTHOR]

Published
2013

445. A model for persistent hole burned spectra and hole growth kinetics that includes photoproduct absorption: Application to free base phthalocyanine in hyperquenched glassy ortho-dichlorobenzene at 5 K.

Author

Reinot, T., Dang, N. C., and Small, G. J.

Subjects
*ABSORPTION spectra, *ENERGY transfer, *ELECTRONIC excitation, *PHTHALOCYANINES, *POLYMERS
Abstract

Persistent nonphotochemical and photochemical hole burning of the S[sub 0]→S[sub 1] origin absorption bands of chromophores in amorphous hosts such as glasses, polymers and proteins at low temperatures have been used to address a number of problems that range from structural disorder and configurational tunneling to excitation energy transfer and charge separation in photosynthetic complexes. Often the hole burned spectra are interfered by photoproduct (antihole) absorption. To date there has been no systematic approach to modeling hole burned spectra and the dispersive kinetics of zero-phonon hole growth that accounts for the antihole. A “master” equation that does so is presented. A key ingredient of the equation is a time-dependent, two-dimensional site excitation frequency distribution function (SDF) of the zero-phonon lines. Prior to hole burning (t=0) the SDF is that of the educt sites. For t>0 the SDF describes both educt and photoproduct sites and allows for burning of the latter that revert to the educt sites from which they originate (light-induced hole filling). Our model includes linear electron–phonon coupling and the three distributions that lead to dispersive hole growth kinetics, the most important of which is the distribution for the parameter λ associated with tunneling between the bistable configurations of the chromophore-host system that are interconverted by hole burning. The master equation is successfully applied to free base phthalocyanine (Pc) in hyperquenched glassy ortho-dichlorobenzene (DCB) at 5 K. The mechanism of hole burning is photochemical and involves tautomerization of the two protons at the center of the macrocycle (Pc) that occurs in the S[sub 1](Q[sub x]) and/or T[sub 1](Q[sub x]) state of Pc. A single set of parameter values (some of which are determined directly from the hole burned spectra) provides a satisfactory description of the dependence of the hole burned spectra and hole growth kinetics on the location of the burn frequency within the inhomogeneously broadened Q[sub x] absorption band. The hole growth kinetics are found to be quite highly dispersive, although to a lesser degree than the kinetics for free base phthalocyanine tetrasulphonate in hyperquenched glassy water [Reinot et al., J. Lumin. 98, 183 (2002)]. The dispersion is attributed to structural heterogeneity of solvent molecules in the inner shell that leads to a distribution of chromophore-host interactions that affect the height of the barrier separating the two tautomers. The new master equation should also prove useful with no additional assumptions or modifications for interpretation of nonphotochemical hole burned spectra. © 2003 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Published
2003
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449. Vascular dementia: galantamine (Reminyl® ) as an emerging therapeutic option.

Author

Small, G. W.

Subjects
*TREATMENT of dementia, *ALZHEIMER'S disease
Abstract

Features the drug galantamine (Reminyl) for vascular dementia. Challenges associated with defining and diagnosing patients with probable vascular dementia or Alzheimer's disease; Role of understanding the pathophysiology of vascular dementia in finding an effective treatment.

Published
2002
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