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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgenic steroids are required to maintain the prostate gland in the adult state. Consistent with this requirement, androgen deprivation therapies typically induce a drastic regression of mature prostate tissue that is accompanied by the extensive loss of prostate cells through the programmed cell death process referred to as apoptosis. Whereas, in the past, the loss of prostate cells associated with androgen deprivation has generally been perceived to be a direct response of the androgen receptor-expressing prostate cells to an androgen-depleted environment, more recent studies of the prostate regression process suggest that it might instead be initiated by an indirect response of the prostatic parenchyma to an ischemic/hypoxic environment caused by a drastic reduction of blood flow to the tissue that occurs when androgens are withdrawn. This article reviews evidence that the prostatic vascular system is a primary target of androgen action and other evidence suggesting that the regression of the prostate parenchyma occurs secondarily to the regression of the prostate vascular system through cell death mediated by tissue ischemia/hypoxia.
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PMID:The effects of androgen deprivation on the prostate gland: cell death mediated by vascular regression. 1100 45

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

Female mice are much more resistant to ischemia/reperfusion (I/R)-induced kidney injury when compared with males. Although estrogen administration can partially reduce kidney injury associated with I/R, we demonstrated that the presence of testosterone, more than the absence of estrogen, plays a critical role in gender differences in susceptibility of the kidney to ischemic injury. Testosterone administration to females increases kidney susceptibility to ischemia. Dihydrotestosterone, which can not be aromatized to estrogen, has effects equal to those of testosterone. Castration reduces the I/R-induced kidney injury. In contrast, ovariectomy does not affect kidney injury induced by ischemia in females. Testosterone reduces ischemia-induced activation of nitric oxide synthases (NOSs) and Akt and the ratio of extracellular signal related kinase (ERK) to c-jun N-terminal kinase (JNK) phosphorylation. Pharmacological (Nomega-nitro-L-arginine) or genetic (endothelial NOS or inducible NOS) inhibition of NOSs in females enhances kidney susceptibility to ischemia. Nitric oxide increases Akt phosphorylation and protects Madin-Darby canine kidney epithelial cells from oxidant stress. Antagonists of androgen or estrogen receptors do not affect the gender differences. In conclusion, testosterone inhibits the post-ischemic activation of NOSs and Akt and the ratio of ERK to JNK phosphorylation through non-androgen receptor-medicated mechanisms, leading to increased inflammation and increased functional injury to the kidney. These findings provide a new paradigm for the design of therapies for ischemia/reperfusion injury and may be important to our understanding of the pathophysiology of acute renal failure in pregnancy where plasma androgen levels are elevated.
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PMID:Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. 1535 59

Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7-8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.
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PMID:Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning. 1679 12

Ginseng root is one of the most popular herbs throughout the world and is believed to be a panacea and to promote longevity. It has been used as a medicine to protect against cardiac ischemia, a major cause of death in the West. We have previously demonstrated that ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes. In this study, we provide compelling evidence that ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K(+) current. The eNOS activation occurs via a nongenomic pathway of each of androgen receptor, estrogen receptor-alpha, and progesterone receptor, in which c-Src, phosphoinositide 3-kinase, Akt, and eNOS are sequentially activated. However, ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen-responsive MCF-7 cells, implying that ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer experiments with a probe, SCCoR (single cell coactivator recruitment), indicate that the lack of genomic action is attributable to failure of coactivator recruitment. Thus, ginsenoside Re acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury.
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PMID:Ginsenoside Re, a main phytosterol of Panax ginseng, activates cardiac potassium channels via a nongenomic pathway of sex hormones. 1698 85

The effect of androgen deprivation and other hormonal therapies, radiation therapy, thermal ablation therapies, chemotherapy, and other systemic treatments is evident in the histology of non-neoplastic and neoplastic human prostate gland. Androgen deprivation may be achieved with: a. orchidectomy, b. exogenous oestrogen administration, c. drugs with the capacity to deplete the hypothalamus of luteinizing hormone-releasing hormone, d. antiandrogens administration: drugs, which block the conversion of testosterone to its active form of 5-alpha dihydrotestosterone (i.e. finasteride, dutasteride), and drugs which block the androgen receptor on individual cells (i.e. flutamide). Androgen deprivation therapies cause atrophy of non-neoplastic and neoplastic prostatic epithelium, as the result of apoptosis, and are mainly used as a palliative measure in metastatic prostate cancer or as neoadjuvant or adjuvant treatment, in clinically localized prostate cancer. Morphological tumour regression may complicate the recognition and grading of treated carcinomas in radical prostatectomy specimens. Radiation therapy may be applied in the form of external beam, interstitial implantation (brachytherapy), or a combination, as a mainstay or adjuvant (external beam) treatment in localized prostate cancer. The primary effect is the damage of endothelial cells, which cause ischemia that leads to atrophy. The difficulty of post-radiation prostate needle biopsy interpretation includes the distinction of treatment effect in normal prostatic tissue from recurrent or residual tumour. Histological changes after thermal ablation mainly include lesions observed in prostatic infarcts due to periurethral coagulative type necrosis of variable volume. The correlation between the histopathological effects of the above therapies and their clinical significance is not absolutely clear.
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PMID:Histopathological changes induced by therapies in the benign prostate and prostate adenocarcinoma. 1712 17

Clinical evidence and animal models indicate greater brain damage in newborn males following injury. In adults, glutamate is the primary source of excitotoxic cell death and the steroid, estradiol, is neuroprotective. In neonatal brain, membrane depolarization following activation of GABAA receptors is the major source of excitation. Consequent influx of calcium via L-type channels is normally trophic, but becomes excitotoxic during periods of excessive activation of GABAA receptors, such as hypoxia-ischemia, alcohol exposure and seizures. The use of sex-specific hippocampal cultures revealed greater cell death induced by the GABAA agonist, muscimol, in male- versus female-derived cultures. Pretreatment with the androgen, dihydrotestosterone (DHT) increased muscimol-induced death in both sexes. Exploration of calcium dynamics indicated that, counter to expectation, female neurons achieved higher [Ca2+]i than male, but the calcium transient duration was shorter due to faster rise and decay. However, a second exposure to muscimol within minutes of the first, caused significant attenuation of [Ca2+]i in female neurons. In contrast, while male neurons exposed to muscimol for the first time exhibited lower maximal [Ca2+]i, when exposed to muscimol again there was no attenuation in [Ca2+]i. The latter effect was induced in females by DHT, and inversely correlated with the amount of gamma2 subunit of the GABAA receptor. This novel effect of androgen on GABA-mediated excitotoxicty suggests a unique opportunity for a sex-specific therapeutic approach involving antagonism of the androgen receptor in neonatal males at risk for brain injury.
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PMID:Androgens predispose males to GABAA-mediated excitotoxicity in the developing hippocampus. 1828 34

Males exhibit greater histologic and behavioral impairment after stroke than do age-matched females. However, the contribution of androgens to stroke outcome remains unclear. We compared outcomes from middle cerebral artery occlusion (MCAO) in castrated mice with those in testosterone- or dihydrotestosterone (DHT)-replaced castrated mice. Castrates treated with 1.5 mg testosterone or 0.5 mg DHT before MCAO showed smaller infarct volumes (hemisphere: 27 or 26%) at 24 h after 90 mins MCAO than did untreated castrates (37%), whereas 5 mg testosterone or 1.5 mg DHT exacerbated infarcts (53 or 51%). These outcomes were blocked by the androgen receptor antagonist, flutamide, suggesting that androgen receptors mediate these responses to ischemia. We further evaluated long-term outcomes with a milder 60-min MCAO in castrates treated with the protective 1.5 mg testosterone dose. Consistent with data obtained at 24 h reperfusion, the infarct volume was decreased at 9 days reperfusion. Neurobehavioral analysis showed that motor functional recovery was improved during the first 3 days of reperfusion, but not improved at 7 days. We conclude that testosterone exhibits dose-dependent and time-sensitive effects after ischemia and that testosterone is likely to be an important factor in sex-linked differences in cerebrovascular disease.
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PMID:Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice. 1943 13

Activation of poly (ADP-ribose) polymerases (PARP) contributes to ischemic damage by causing neuronal nicotinamide adenine dinucleotide (NAD(+)) depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. We observed smaller damage following focal cerebral ischemia (MCAO) in male PARP-1 knockout mice compared to wild type (WT) as well as decreased damage in male mice treated with the PARP inhibitor PJ34. Protection from ischemic damage provided by PJ-34 in WT mice is lost after removal of testicular androgens (CAST) and rescued by androgen replacement. CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicate that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.
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PMID:Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway--do androgens matter? 2003 40

The molecular mechanisms that lead to ischemic pre-conditioning are not completely understood, and proteins are important players. We compared the mouse brain cortex proteome from different ischemia sets: transient (7 min) middle cerebral artery occlusion (7'MCAo, pre-conditioning stimulus), permanent MCAo (pMCAo, severe ischemia), and pMCAo 4 days after 7'MCAo (7'MCAo/pMCAo, pre-conditioned model). Proteins were analyzed by two-dimensional electrophoresis coupled to liquid chromatography-tandem mass spectrometry. Overall, 28 proteins were expressed differentially from sham controls, and identified. The ischemic pre-conditioning stimulus alone up-regulated the stress protein heat-shock protein 70 (HSP70), possibly activated by the androgen receptor. Western blotting confirmed the increased expression of HSP70 and showed that androgen receptor expression paralleled that of HSP70. In the ischemic-tolerant group (7'MCAo/pMCAo), a number of proteins over-expressed after pMCAo returned to sham levels, seven proteins remained up-regulated as in pMCAo, and five proteins mainly involved in energy metabolism and mitochondrial electron transport and unchanged in pMCAo were down-regulated only in ischemic tolerance, suggesting a role in brain pre-conditioning. Astrocytes participated in ischemic-tolerance induction, as shown by the down-regulation of glutamine synthetase in the 7'MCAo/pMCAo group. The results suggest that metabolic down-regulation was a general feature of ischemic pre-conditioning, playing a pivotal role in neuroprotection.
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PMID:Proteomic analysis of mouse brain cortex identifies metabolic down-regulation as a general feature of ischemic pre-conditioning. 2280 28


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