Although currently no drugs that specifically target mitochondrial biogenesis in HF are available, acceleration of this process through adenosine monophosphate–activated kinase (AMPK), endothelial nitric oxide synthase (eNOS), and other pathways may represent a promising therapeutic approach
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Peripheral mechanisms of erectile dysfunction in a rat model of chronic cocaine use. - ... - 0 views
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American College of Cardiology Foundation | Journal of the American College of Cardiolo... - 0 views
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Mitochondrial biogenesis can be enhanced therapeutically with the use of adenosine monophosphate kinase (AMPK) agonists, stimulants of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway (including phosphodiesteraes type 5 inhibitors), or resveratrol
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Recent evidence suggests that the eNOS/NO/cGMP pathway is an important activator of mitochondrial biogenesis
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BH4 (tetrahydrobiopterin) supplementation can prevent eNOS uncoupling and was found to reduce left ventricular hypertrophy
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folic acid is known to replenish reduced BH4 and has been shown to protect the heart through increased eNOS activity
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Both folate deficiency and inhibition of BH4 synthesis were associated with reduced mitochondrial number and function
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Resveratrol, a polyphenol compound responsible for the cardioprotective properties of red wine, was recently identified as a potent stimulator of mitochondrial biogenesis
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epidemiological studies reveal a reduced risk of cardiovascular disease in premenopausal, but not post-menopausal, women compared with men
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post-menopausal women
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The majority of ROS in the heart appear to come from uncoupling of mitochondrial electron transport chain at the level of complexes I and III
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Because the majority of ROS in HF comes from mitochondria, these organelles are the primary target of oxidative damage.
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cardioprotective therapies such as angiotensin-converting enzyme inhibitors and ATII receptor blockers were shown to possess antioxidant properties, although it is not known whether they target mitochondrial ROS directly or indirectly
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shared by Nathan Goodyear on 13 May 13
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Testosterone: a vascular hormone in health and disease - 0 views
joe.endocrinology-journals.org/...R47.full
testosterone hormone health disease hormones men male cardiovascular disease CVD
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Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
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In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.
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testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells
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Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis
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there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
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bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors
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Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function
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It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years
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no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
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free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD
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Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans
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Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
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Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production
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In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
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the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development
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Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone
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acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription
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Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition
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non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
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increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells
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Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
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Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism
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TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
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testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
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Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
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Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells
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decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT
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The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
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Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
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As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
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prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone
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DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes
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(Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol
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TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs
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3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
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This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.
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The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
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There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality
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The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
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trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months
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Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action
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The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.
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the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms
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http://circres.ahajournals.org/content/circresaha/92/1/88.full.pdf - 0 views
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Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intrace... - 0 views
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Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activit... - 0 views
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http://circ.ahajournals.org/content/circulationaha/107/18/2348.full.pdf - 0 views
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shared by Nathan Goodyear on 14 Sep 17
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5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide... - 0 views
circ.ahajournals.org/...1193.long
BH4 5-methyltetrahydrofolate tetrahydrobiopterine MTHFR MTHFR A1298C eNOS NO nitric oxide atherosclerosis cardiovascular disease CVD
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Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activit... - 0 views
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IV Vitamin C improves endothelial vasodilation in essential hypertension. The Vitamin C reduces the oxygen free radicals which allowed eNOS to increase NO production. Two take homes: oxygen free radicals may be responsible for the endothelial dysfunction that leads to essential hypertension and vitamin C, particularly IV, can be used to counter this process. Other studies have shown IV vitamin C to be anti-hypertensive in its action.
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Journal of Clinical Investigation -- Oxidation of tetrahydrobiopterin leads to uncoupli... - 0 views
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at hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS
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Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.
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shared by Nathan Goodyear on 03 Sep 17
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Chronic stress impacts the cardiovascular system: animal models and clinical outcomes |... - 0 views
ajpheart.physiology.org/...H1476
chronic stress stress inflammation cardiovascular disease atherosclerosis NO nitric oxide oxidative stress cardiovascular heart
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Chronic stress increases cardiovascular disease. Of note, chronic stress reduces eNOS activity and NO bioavailability, increased lipid oxidation (oxLDL) via a reduction in antioxidant protection, increased pro-inflammatory cytokines, increased thrombosis and clotting risk, increased blood pressure and reduced HRV.
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ScienceDirect - Pharmacological Research : Antioxidants to enhance fertility: Role of e... - 0 views
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shared by Nathan Goodyear on 29 Feb 12
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Septic impairment of capillary blood flow requires NADPH oxidase but not NOS and is rap... - 0 views
www.ncbi.nlm.nih.gov/...PMC2572871
IV intravenous vitamin C BH4 tetrahydrobiopterine sepsis ascorbic acid
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Equine Estrogens Impair Nitric Oxide Production and Endothelial Nitric Oxide ... - 0 views
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This is the perfect study to compare synthetic, unnatural hormones with bioidentical hormones. Premarin was compared with bioidentical estradiol. Premarin reduced the endothelial NO synthase transcription and activity by 30-50% compared to Estradiol. Thus, premarin results in a lower NO production and thus greater endothelial dysfunction compared to Estradiol.
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Long-Term Vitamin C Treatment Increases Vascular Tetrahydrobiopterin Levels and Nitric ... - 0 views
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beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity
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ScienceDirect - 0 views
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How is the Immune System Suppressed by Cancer - 1 views
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Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
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The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
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nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
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NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
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Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
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Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
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Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10. IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
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Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
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Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
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Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
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IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
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nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
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early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
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later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
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elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
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The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells. Histamine alone stimulates many tumor cells.
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last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
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intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
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In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
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Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
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Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
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Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
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Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
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In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
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these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
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Communication between genomic and non-genomic signaling events coordinate steroid hormo... - 0 views
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steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
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This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
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In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
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the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
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Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
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NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
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Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
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ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
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G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
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androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
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non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
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Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
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ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
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A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
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androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
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However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
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estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways