Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation.

Eich, David M.; Nestler, John E.; Johnson, Danna E.; Dworkin, Gary H.; Ko, Daijin; Wechsler, Andrew S.; Heß, Michael

doi:10.1161/01.cir.87.1.261

Cited by 117 publications

(47 citation statements)

References 28 publications

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“…In the donor hearts, 827 vessels in the control group and 617 vessels in the CS1-treated tim), medium (diameter > 100 < 500 ,m), and large (diameter > 500 Jsm). The degree of intimal thickening was then quantitatively assessed in each vessel size category as previously described (36 vat pentachrome-stained histologic sections, we observed a similar small proportion of coronary arteries with intimal thickening in host hearts from both control (scrambled peptide) and CS1-treated groups (10±1 and 12±2% SEM, respectively) ( Fig. 1).…”

Section: Introductionmentioning

confidence: 56%

Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Molossi¹,

Elices²,

Arrhenius³

et al. 1995

J. Clin. Invest.

102

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Graft arteriopathy, a leading cause of cardiac allograft failure, is associated with increased intimal smooth muscle cells, inflammatory cells, and accumulation of extracellular matrix. We hypothesized that cellular fibronectin plays a pivotal role in the progression of the allograft arteriopathy by directing the transendothelial trafficking of inflammatory cells through interaction of the connecting segment-i (CS1) motif with the very late antigen-4 (VLA-4) integrin, and tested this in vivo using a blocking peptide. Cholesterolfed rabbits underwent heterotopic cardiac transplantation without immunosuppression. The treatment group (n = 7) received a synthetic CS1 peptide (1 mg/kg per d, subcutaneously), and the controls (n = 7) received an inactive peptide (1 mg/kg per d, subcutaneously). At 7-8 d after transplantation, hearts were harvested and sectioned for morphometric analysis and immunohistochemical studies. We observed a > 50% decrease in the incidence (P < 0.001) and severity (P < 0.001) of donor coronary artery intimal thickening in the CS1-treated compared with the control group. These findings correlated with reduced infiltration of T cells (P < 0.05), a trend toward decreased expression of adhesion molecules (P < 0.06), and less accumulation of fibronectin (P < 0.03). Our data suggest that the VLA-4-fibronectin interaction is critical to the progression of the allograft arteriopathy by perpetuating the immune-inflammatory response in the vessel wall. (J. Clin. Invest 1995Invest . 95:2601Invest -2610

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Section: Introductionmentioning

confidence: 56%

Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Molossi¹,

Elices²,

Arrhenius³

et al. 1995

J. Clin. Invest.

102

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“…The re-port by Roth [2] shows that the lifespan of a person and the serum concentration of DHEA are related. There are also reports related to antiatherosclerotic [3][4][5][6], antidiabetic [7][8][9], antiinflammatory [10][11][12], and antiosteoporotic functions [13,14], and we anticipate that DHEA has the so-called antisenility hormone function related to the aging phenomenon.…”

mentioning

confidence: 88%

Changes in Serum Sex Hormone Profiles after Short-term Low-dose Administration of Dehydroepiandrosterone (DHEA) to Young and Elderly Persons

et al. 2007

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Abstract. In man, serum concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease with age after the twenties. For this reason, the decline in DHEA and DHEAS concentrations may be related to the development of some chronic diseases that are prevalent in the older age population. In this study, we evaluate the benefit and safety level of DHEA administration to men as a hormone replacement therapy. Twenty-two healthy Japanese males (age 26-63; mean ± SD, 41.0 ± 10.0 yrs.) received 25 mg DHEA once a day orally in the morning for two weeks. Serum concentrations of steroid hormones and cytokines were measured before and after the DHEA administration. Glucose tolerance and insulin resistance were also assessed before and after the DHEA administration using a 75 g oral glucose tolerance test and homeostasis model assessment (HOMA-R), respectively. Serum DHEA and DHEAS levels were significantly elevated after the DHEA administration for all ages of test subjects. In subjects who were older than 41 yrs. (older group) serum androstenedione and estradiol levels were elevated after the DHEA administration. Significant negative correlations were observed between the serum DHEA concentration and the serum concentration of fasting insulin, HOMA-R, leptin, and high-sensitivity C-reactive protein for all subjects. Daily administration of 25 mg DHEA increased the serum DHEA, DHEAS, androstenedione, and estradiol levels of the subjects of the older group to the same level as that of younger subjects. WHILE it is known that there is an abundance of dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) in the peripheral circulation in humans, their essential physiological roles still remain unclear. It is known that the secretion of DHEA increases with postnatal aging peaking in the twenties, and then decreases with age afterwards. Due to this type of dynamic change, the decline in DHEA and DHEAS secretion based on aging is compared to female menopause and expressed as adrenopause. The relationship of DHEA and DHEAS to symptoms of senility and geriatric disease has attracted much attention [1]. The re-

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“…The severity of intimal thickening was quantitatively assessed in each affected vessel according to a method previously described. 30 The areas encompassed by the outer medial layer (ML), the internal elastic lamina (IEL), and the lumen were measured, and the area of intimal thickening (IT) related to the vessel area was calculated by the formula:…”

Section: Quantitative Assessment Of Coronary Arteries By Light Microsmentioning

confidence: 99%

In vivo blockade of tumor necrosis factor-alpha in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation.

et al. 1994

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BACKGROUND We previously identified in piglet cardiac allografts an immunoinflammatory response in coronary arteries in which increased fibronectin regulated by interleukin-1 beta was associated with early evidence of intimal thickening. In the present study, we used rabbits to assess whether acute neointimal formation after cardiac transplantation was reduced by blockade of tumor necrosis factor (TNF)-alpha, which modulates interleukin-1 beta, or by cyclosporine A. METHODS AND RESULTS Sixteen rabbits underwent heterotopic cardiac transplantation and were given saline, TNF-soluble receptor (sr), or cyclosporine A. In host hearts from saline- or TNFsr-treated groups, few coronary arteries (approximately 13% to 16%) had intimal thickening, whereas values were higher in the cyclosporine A-treated group (approximately 30%). In donor hearts from the saline-treated group, however, approximately 68% of vessels had intimal thickening versus approximately 32% in TNFsr- and approximately 30% in cyclosporine A-treated groups (P < .01 for both). Severity of intimal thickening assessed quantitatively as percent vessel area was approximately 38% in the saline-treated group but reduced in TNFsr- and cyclosporine A-treated groups to approximately 22% and 18%, respectively (P < .01 for each). Immunohistochemistry revealed increased staining for major histocompatibility complex II, T cells, interleukin-1 beta, TNF-alpha, and fibronectin in donor coronary arteries from saline-treated animals when compared with TNFsr- and cyclosporine A-treated animals. Grade 3 myocardial rejection was observed in both saline- and TNFsr-treated groups, but only grade 1 was apparent in the cyclosporine A-treated group. CONCLUSIONS In vivo blockade of TNF-alpha suppresses the acute development of neointimal formation by selectively reducing the vascular immunoinflammatory reaction and accumulation of fibronectin, whereas cyclosporine A suppresses both the myocardial and the vascular immune reaction.

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Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation.

Abstract: It is concluded that chronic DHEA administration in a hypercholesterolemic rabbit model of heterotopic cardiac transplantation significantly retards the progression of accelerated atherosclerosis in both the transplanted heart and in the native heart.

Cited by 117 publications

References 28 publications

Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Changes in Serum Sex Hormone Profiles after Short-term Low-dose Administration of Dehydroepiandrosterone (DHEA) to Young and Elderly Persons

In vivo blockade of tumor necrosis factor-alpha in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation.

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