Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the direct effect of androgen on the development of atherosclerosis, we investigated the effect of androgen and its receptor expression in rat vascular smooth muscle cells (VSMC) isolated from rat aorta. We detected the androgen receptor mRNA in VSMC by reverse transcription of the total RNA coupled with amplification of the resulting cDNA by polymerase chain reaction. Binding studies revealed the presence of a single class of binding sites for testosterone (Kd 7.37 nM, Bmax 10.59 fmol/mg protein) and dihydrotestosterone (DHT; Kd 4.89 nM, Bmax 11.37 fmol/mg protein) in VSMC. Measurement of 5 alpha-reductase activity suggested that testosterone is converted to DHT in VSMC (Km 0.36 microM, Vmax 623 fmol/mg protein/h). Moreover, in the present study, DHT significantly stimulated DNA synthesis of VSMC (120-160% of control). The mitogenic activity of testosterone is much less potent than that of DHT. Considering these results, we concluded that androgen may directly accelerate atherosclerosis by stimulating the proliferation of VSMC.
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PMID:Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells. 804 46

X chromosome inactivation studies indicate that smooth muscle cells in human atherosclerosis are monoclonal. Monoclonality could arise either by 1) proliferation of a single cell in the adult intima, eg, by selection or mutation, or 2) proliferation of many cells within a large, pre-existing clonal patch that formed during development. To determine whether clonal expansion occurs concomitantly with plaque growth or as part of normal development, X chromosome inactivation patterns were mapped in microdissected samples of aortic smooth muscle, using the human androgen receptor locus as a marker. As expected, 43% of plaque samples were skewed toward one X chromosome, indicating a monoclonal population. Surprisingly, 25% of normal medial samples and 31% of diffuse intimal thickening samples also were skewed toward one X chromosome, indicating a relatively large patch size. Furthermore, 30% of diffuse intimal thickening and 22% of medial samples showed contiguous regions of 4 mm skewed to the same allele, showing that patch length often exceeded 4 mm. Intima and overlying media typically were skewed to the same allele (73% concordance), suggesting common cells of origin. Because patch size is large in normal arteries, X-inactivation analysis cannot discriminate between a monoclonal and a polyclonal origin of plaque smooth muscle cells. We propose that human arteries grow by expanding coherent smooth muscle clones, with little mixing of adjacent clones. Determining whether plaques arise by clonal expansion will require other approaches, such as analysis of somatic mutations; the finding of large X-inactivation patches raises the possibility that plaques arise from a pre-existing (developmental) clone.
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PMID:Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. 954 52

The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308+/-39) and lowest in the TE group (61+/-12), but was intermediate in the DHEA (155+/-30), TU (191+/-43), and sham operation (162+/-29) groups (ANOVA, P<0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect.
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PMID:Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. 1020 49

We investigated the effect of testosterone (T) on tumor necrosis factor-alpha (TNF-alpha)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells. Incubation of these cells with T resulted in a dose-dependent reduction in the expression, with this reduction completely abolished by a selective androgen receptor blocker. Electrophoretic mobility shift assay demonstrated that T inhibited TNF-alpha-induced activation of the transcriptional nuclear factor-kappaB, which is critical for the inducible expression of VCAM-1, probably through the suppression of the nuclear translocation. Our results may suggest an inhibitory effect of T on atherogenesis, providing a novel insight into the consideration of the pathogenesis of atherosclerosis.
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PMID:Testosterone inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells. 1238 79

Globally, cardiovascular disease will continue causing most human deaths for the foreseeable future. The consistent gender gap in life span of approximately 5.6 yr in all advanced economies must derive from gender differences in age-specific cardiovascular death rates, which rise steeply in parallel for both genders but 5-10 yr earlier in men. The lack of inflection point at modal age of menopause, contrasting with unequivocally estrogen-dependent biological markers like breast cancer or bone density, makes estrogen protection of premenopausal women an unlikely explanation. Limited human data suggest that testosterone exposure does not shorten life span in either gender, and oral estrogen treatment increases risk of cardiovascular death in men as it does in women. Alternatively, androgen exposure in early life (perinatal androgen imprinting) may predispose males to earlier onset of atherosclerosis. Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in the progression of cardiovascular disease, highlighting the need to better understand androgen receptor (AR) coregulators, nongenomic androgen effects, tissue-specific metabolic activation of androgens, and androgen sensitivity. Novel therapeutic targets may arise from understanding how androgens enhance early plaque formation and cause vasodilatation via nongenomic androgen effects on vascular smooth muscle, and how tissue-specific variations in androgen effects are modulated by AR coregulators as well as metabolic activation of testosterone to amplify (via 5alpha-reductase to form dihydrotestosterone acting on AR) or diversify (via aromatization to estradiol acting upon estrogen receptor alpha/beta) the biological effects of testosterone on the vasculature. Observational studies show that blood testosterone concentrations are consistently lower among men with cardiovascular disease, suggesting a possible preventive role for testosterone therapy, which requires critical evaluation by further prospective studies. Short-term interventional studies show that testosterone produces a modest but consistent improvement in cardiac ischemia over placebo, comparable to the effects of existing antianginal drugs. By contrast, testosterone therapy has no beneficial effects in peripheral arterial disease but has not been evaluated in cerebrovascular disease. Erectile dysfunction is most frequently caused by pelvic arterial insufficiency due to atherosclerosis, and its sentinel relationship to generalized atherosclerosis is insufficiently appreciated. The commonality of risk factor patterns and mechanisms (including endothelial dysfunction) suggests that the efficacy of antiatherogenic therapy is an important challenge with the potential to enhance men's motivation for prevention and treatment of cardiovascular diseases.
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PMID:Androgens and cardiovascular disease. 1278 2

There exists a striking gender difference in atherosclerotic vascular disease. For decades, estrogen was considered atheroprotective; however, an alternative is that androgen exposure in early life may predispose men to earlier atherosclerosis. We recently demonstrated that the potent androgen, dihydrotestosterone (DHT), enhanced the binding of monocytes to the endothelium, a key early event in atherosclerosis, via increased expression of vascular cell adhesion molecule-1 (VCAM-1). We now show that DHT mediates its effects on VCAM-1 expression at the promoter level through a novel androgen receptor (AR)/nuclear factor-kappaB (NF-kappaB) mechanism. Human umbilical vein endothelial cells were exposed to 4-400 nm DHT. DHT increased VCAM-1 mRNA in a dose- and time-dependent manner. The DHT effect could be blocked by the AR antagonist, hydroxyflutamide. DHT increased VCAM-1 promoter activity via NF-kappaB activation without affecting VCAM-1 mRNA stability. Using 5' deletion analysis, it was determined that the NF-kappaB sites within the VCAM-1 promoter region were responsible for the DHT-mediated increase in VCAM-1 expression; however, coimmunoprecipitation studies suggested there is no direct interaction between AR and NF-kappaB. Instead, DHT treatment decreased the level of the NF-kappaB inhibitory protein. DHT did not affect VCAM-1 protein expression and monocyte adhesion when female endothelial cells were tested. AR expression was higher in male, relative to female, endothelial cells, associated with increased VCAM-1 levels. These findings highlight a novel AR/NF-kappaB mediated mechanism for VCAM-1 expression and monocyte adhesion operating in male endothelial cells that may represent an important unrecognized mechanism for the male predisposition to atherosclerosis.
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PMID:Dihydrotestosterone promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kappaB-dependent pathway. 1468 16

Vascular smooth muscle cell (VSMC) proliferation and proteoglycan biosynthesis are two critical contributors to the development of atherosclerosis. We investigated the effects of specific androgens, androstenedione, dihydrotestosterone, and testosterone, on proteoglycan biosynthesis in human VSMC derived from internal mammary arteries. Vascular SMCs were metabolically labeled with [(35)S]sulfate or [(35)S]methionine/cysteine to assess glycosaminoglycans (GAGs) or proteoglycan core protein, respectively. The electrophoretic migration of radiolabeled proteoglycans was assessed by SDS-PAGE. Proteoglycan-low density lipoprotein (LDL) interactions were assessed using LDL affinity columns. Treatment of VSMCs with androstenedione (100 nm), dihydrotestosterone (10 nm), or testosterone (100 nm) increased [(35)S]sulfate incorporation into GAGs by 24.8% (P < 0.05), 22% (P < 0.05), and 32.5% (P < 0.05), respectively. Treatment of VSMCs with testosterone did not alter [(35)S]methionine/cysteine incorporation into proteoglycan core protein, suggesting that the effect of testosterone was associated with an increase in GAG length. Dihydrotestosterone (10 nm) and testosterone (100 nm) treatment of VSMCs resulted in the synthesis of biglycan and decorin that showed reduced electrophoretic mobility by SDS-PAGE, indicating an increase in GAG length. The effect of testosterone treatment on [(35)S]sulfate incorporation and GAG length was reversed by pretreatment of VSMCs with flutamide (1 mum), an androgen receptor antagonist. Proteoglycans from VSMCs treated with testosterone showed 11% (P < 0.01) higher binding capacity to LDL compared with proteoglycans from untreated cells. These results suggest a possible proatherogenic action of androgens through an elongation of GAG chains on proteoglycans in an androgen receptor-dependent manner.
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PMID:Androgens stimulate human vascular smooth muscle cell proteoglycan biosynthesis and increase lipoprotein binding. 1566 61

There are gender differences in the development of atherosclerosis, possibly owing to differences in sex steroid hormone action and/or metabolism. One of the atherogenic effects of testosterone is thought to be androgen receptor (AR)-mediated vascular smooth muscle cell (VSMC) proliferation. However, the detailed mechanism of this effect, particularly the identity of the genes associated with VSMC proliferation, remains largely unknown. Therefore, we first employed microarray analysis and, subsequently, quantitative RT-PCR to analyse RNA expression in AR-positive human VSMCs treated with testosterone in order to detect testosterone-induced genes associated with cell proliferation. We further examined whether the genes identified were involved in cell proliferation using small interfering RNA (siRNA) transfection. Expression of the gene products was then evaluated in human aorta with various degrees of atherosclerosis in order to evaluate the clinical relevance of the findings. Both microarray and quantitative RT-PCR analyses demonstrated marked induction of the human prostate overexpressed protein 1 (PTOV1) gene by testosterone in the cell lines: this gene was recently identified as a novel androgen-induced gene involved in prostate tumour cell proliferation. Inhibition of PTOV1 by transfection of its corresponding siRNA suppressed testosterone-induced cell proliferation. In human aorta, PTOV1 immunoreactivity in the nuclei of neointimal VSMCs was abundantly detected in male aorta with mild atherosclerotic changes compared with female aorta or male aorta with severe atherosclerotic changes. These findings indicate that the PTOV1 gene is androgen-responsive in VSMCs and that it may play an important role in androgen-related atherogenesis in the human aorta, particularly early atherosclerosis in the male aorta, through regulating proliferation of neointimal VSMCs.
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PMID:PTOV1: a novel testosterone-induced atherogenic gene in human aorta. 1663 97

The role of testosterone in atherosclerosis remains unclear because it is aromatized to estrogen. We investigated the effect of the nonaromatized natural androgen 5alpha-dihydrotestosterone (DHT) on the rabbit atherogenesis in relation to the proatherogenic molecule lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1) and its downstream molecules. Thirty-nine male New Zealand white rabbits were divided into four groups: 1) noncastrated group with normal chow diet (n = 6); 2) noncastrated group with high-cholesterol diet (HCD) (n = 10); 3) castrated group with HCD plus sc placebo pellet (n = 11); and 4) castrated group with HCD plus sc 150 mg DHT pellet (n = 12). Implantation of sc DHT or placebo pellet was performed at the time of castration. After castration or sham operation, the rabbits were fed the HCD for 8 wk, and plaque areas were assessed in the entire aorta. The HCD-induced increase in plaque area, which was most aggravated in the castration plus placebo group, was attenuated in the castration plus DHT group. Microscopic examination of the proximal descending aorta revealed that DHT significantly reduced HCD-induced foam cell formation, which was mostly composed of macrophages in the intima layer, compared with the placebo group. The decreased accumulation of foam cells with DHT treatment was accompanied by a marked reduction in the expression of LOX-1 mRNA in these cells. In cultured macrophages prepared from male wild-type mice that express the androgen receptor (AR), 1 x 10(-8) m and 1 x 10(-9) m DHT inhibited the formation of foam cells induced by oxidized low-density lipoprotein. Moreover, the expression of LOX-1 and inflammatory cytokines in the cultured macrophages was significantly suppressed by DHT. Such suppressive effects of DHT on foam cell formation and cytokine expression were not observed in cultured macrophages prepared from male AR-null mice, suggesting an involvement of AR in the mechanism. In conclusion, physiological levels of DHT attenuated the development of atherosclerosis in rabbits through the suppression of intimal foam cell formation of macrophage partly via the suppression of LOX-1 expression.
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PMID:Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. 2042 82

The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.
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PMID:Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. 2086 Dec 31


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