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Posts Tagged ‘Royal Society’


Reporter: Aviva Lev-Ari, PhD, RN

Prostacyclin and Nitric Oxide: Adventures in vascular biology –  a tale of two mediators

The e-Readers are encouraged to review two additional Sources on this topic on this Open Access Online Scientific Journal

Perspectives on Nitric Oxide in Disease Mechanisms

 and

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

S Moncada*

The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK
* (Email: s.moncada@ucl.ac.uk)

Prof. Moncada:

I would like to thank the Royal Society for inviting me to deliver the Croonian Lecture. In so doing, the Society is adding my name to a list of very distinguished scientists who, since 1738, have preceded me in this task. This is, indeed, a great honour.

For most of my research career my main interest has been the understanding of the normal functioning of the blood vessel wall and the way this is affected in pathology. During this time, our knowledge of these subjects has grown to such an extent that many people now believe that the conquering of vascular disease is a real possibility in the foreseeable future.

My lecture concerns the discovery of two substances, prostacyclin and nitric oxide. I would like to describe the moments of insight and some of the critical experiments that contributed significantly to the uncovering of their roles in vascular biology. The process was often adventurous, hence the title of this lecture. It is the excitement of the adventure that I would like to convey in the text that follows.

Keywords: prostacyclin, aspirin, nitric oxide, oxidative stress, free radicals, cardiovascular pathology
Full article 
Philos Trans R Soc Lond B Biol Sci. 2006 May 29; 361(1469): 735–759.
Published online 2006 February 8. doi:  10.1098/rstb.2005.1775
PMCID: PMC1609404

9. THE TWO STORIES CONVERGE

Although the research fields of prostacyclin/thromboxane and NO are now mature, they have developed mostly as parallel research activities with few points of contact between them. Thus, our understanding of how both might operate in relation to each other in physiology and pathophysiology remains to be developed. Table 2 shows some of the similarities between prostacyclin and NO. Both mediators, from very different biochemical pathways, play a variety of roles in the modulation and protection of the vascular wall. The release of both mediators is dependent on constitutive enzymes, the activity of which seems to be regulated locally, predominantly by the shear stress caused by the blood passing over the endothelial surface (Grabowski et al. 1985Frangos et al. 1985; for review see Boo & Jo 2003). However, while the constitutive eNOS—localized only in the vascular endothelium—is the enzyme that responds to shear stress, the generation of prostacyclin is dependent on the activity of two enzymes, COX-1 and COX-2, in relation to which several questions remain unanswered. These include whether COX-2 is a constitutive as well as an inducible enzyme, and whether COX-1 or COX-2, or both, respond to shear stress by increases in their mRNA, their activity, or both (Topper et al. 1996Okahara et al. 1998;McCormick et al. 2000Garcia-Cardena et al. 2001). Prostacyclin, unlike NO, is constitutively generated throughout the vessel wall (Moncada et al. 1977c) and at this stage we also do not know whether the ratio between COX-1 and COX-2 changes in the different layers. In addition, the similarities and differences between regulation of NO and prostacyclin by shear stress are only now being investigated (Osanai et al. 2000McAllister et al. 2000Walshe et al. 2005).

Table 2

Table 2

Comparison of the properties of nitric oxide and prostacyclin.

A clear synergism between NO and prostacyclin has been demonstrated in regard to inhibition of platelet aggregation; however, only one of them (NO) plays a role in inhibiting platelet adhesion. The significance of this difference remains to be understood. Many years ago a physiological role for platelets in repairing the vessel wall was investigated (for discussion see Higgs et al. 1978). This subject has not been re-evaluated in the light of all this new knowledge about the roles of NO and prostacyclin in platelet/vessel wall interactions. Both mediators also regulate vascular smooth muscle proliferation and white cell vessel wall interactions through similar mechanisms which include, at least in part, the activation of adenylate cyclase and the soluble guanylate cyclase. The interactions between NO and prostacyclin in the control of these functions are not fully understood.

Both mediators are further increased by inflammatory stimuli; however, while in the case of prostacyclin the same COX-2 which responds to shear stress responds to such stimuli by a further increase in its expression, NO is generated during inflammation by a specific ‘inducible’ NO synthase which is not normally present physiologically in the vessel wall. The induction of both is inhibited by anti-inflammatory glucocorticoids (Axelrod 1983Knowles et al. 1990). It is remarkable that both compounds possess antioxidant properties (Wink et al. 1995Egan et al. 2004) but are themselves affected by oxidative stress, which inhibits the synthesis of prostacyclin and decreases the bioavailability of NO. This mechanism might be relevant to the ‘malfunctioning’ of the constitutive generation of both mediators and therefore to the genesis of endothelial dysfunction. This, however, is an early phenomenon. In advanced disease the situation is far more complex, akin to chronic inflammation in other parts of the body and, as such, probably varies significantly in the different stages of the disease. A simple hypothesis would suggest that any amount of prostacyclin which is bioavailable, although pro-inflammatory, will provide anti-thrombotic protection, while in the case of NO the balance will vary between bioavailable NO which is protective and cytotoxic peroxynitrite formed from the interaction of NO with O2. Currently, however, the results are not clear and on the crucial question of the role of both mediators in the progression of atherosclerosis, the information in relation to prostacyclin is contradictory (Burleigh et al. 2002Olesen et al. 2002Rott et al. 2003). The evidence in relation to NO, on the other hand, seems to suggest that, while constitutive NO generated by eNOS is protective (e.g. Kawashima & Yokoyama 2004), NO generated by the inducible enzyme favours the development of atherosclerosis (Chyu et al. 1999). Studies of genetically manipulated animals are providing some important clues. For example, knockout of the prostacyclin receptor (IP) leads to mice with normal blood pressure but an increased tendency to thrombosis when the endothelium is damaged (Murata et al. 1997) These animals also exhibit an increased platelet activation and proliferative response to injury that can be prevented by deletion or antagonism of the TXA2 receptor (Cheng et al. 2002). Furthermore, deletion of the IP receptor in animals prone to spontaneous atherosclerosis accelerates the development of the disease (Egan et al. 2004;Kobayashi et al. 2004). On the other hand, knocking out the thromboxane receptor or the thromboxane synthase gives rise to a mild bleeding tendency and a resistance to platelet aggregation and sudden death induced by arachidonic acid infusion (Thomas et al. 1998Yu et al. 2004). Deletion of the thromboxane receptor also seems to retard atherogenesis in murine models of atherosclerosis (Cayatte et al. 2000;Egan et al. 2005).

Although the lack of either mediator has been shown to increase the risk of thrombosis and atherosclerosis, especially in animals with additional risk factors such as ApoE deficiencies (Kuhlencordtet al. 2001Belton et al. 2003), there seems to be a certain specialization in their actions, so that NO has a more significant role in the regulation of blood pressure and blood flow, while prostacyclin has a clearer role in regulating platelet/vessel wall interactions. For example, inhibition of NO generation has an immediate and dramatic effect on blood flow and blood pressure and the eNOS−/− animal exhibits a clear hypertensive phenotype. On the other hand, inhibition of prostacyclin synthesis by the coxibs leads to a slow effect on blood pressure and apparently to a more thrombotic situation (Muscara et al. 2000;FitzGerald 2003). Similarly, COX-1−/− and COX-2−/− animals show no change in blood pressure (Norwood et al. 2000Cheung et al. 2002) and manipulation of COX or IP results in a prothrombotic phenotype.

Protection against decreases in the generation of constitutive NO and prostacyclin in the vasculature may prevent the development of vascular disease. In relation to NO, the most often tried interventions relate to the use of antioxidants (see Carr & Frei 2000) and the manipulation of eNOS expression by genetic means (Von der Leyen & Dzau 2001). Each of these interventions has shown promise in both animal experiments and in humans. An unexpected and highly interesting development relates to the effects of statins which, in the last few years, have been shown to increase the production of endothelial NO in endothelial cell cultures and in animals (for review see Laufs 2003). Many mechanisms have been claimed for this action. However, of interest in the context of our discussion is the fact that statins have been claimed to reduce oxidative stress by increasing the synthesis of BH4 (Hattori et al. 2002), increasing the coupling of the eNOS (Brouet et al. 2001) or reducing the activation of NADPH oxidase (Wagner et al. 2000). Reduction of oxidative stress is likely to preserve the generation of prostacyclin, and to our knowledge there is at least one report suggesting that statins also increase prostacyclin in endothelial cell cultures of human coronary arteries (Mueck et al. 2001). Studies on the transfection of COX-1 or COX-2 into endothelial and other cells, on the other hand, are at an early stage and clear results are not conclusive (Murakami et al. 1999Shyue et al. 2001). The full consequences of overexpression of both NO and prostacyclin in the vasculature remain to be investigated.

Also relevant to this discussion are studies of the role that NO and prostacyclin play in the protection of the cardiovascular system provided by oestrogens, and therefore in the difference between genders in susceptibility to cardiovascular disease. Oestrogens increase the expression and the activity of eNOS (Weiner et al. 1994Yang et al. 2000) and the activity of the COX-2 enzyme (Akarasereenont et al. 2000;Egan et al. 2004). They could therefore reduce oxidative stress by simply increasing both mediators. Alternatively, it has been claimed that oestrogens increase the efficiency of the NO synthase, thus reducing free radical formation (Barbacanne et al. 1999).

In summary, the concept of the balance between prostacyclin and TXA2 has to be expanded to include NO. Furthermore, although not discussed in this review, the way in which these compounds interact with many other systems known to be involved in vessel wall physiology and pathophysiology requires further investigation. Both prostacyclin and NO synergize in the protection of the vessel wall. TXA2, however, lies on the negative side of this balance being responsible for, among other things, platelet aggregation and vasoconstriction. The investigation into the interplay between these three molecules is just beginning. This is a sobering thought when one is contemplating probably close to 100 000 papers and over 30 years of research! However, it is clear that the discoveries of prostacyclin and NO have transformed our comprehension of vascular physiology and opened avenues for further understanding of pathophysiological processes. This knowledge has already benefited clinical medicine and no doubt will continue providing clues that will guide future therapy and prevention of vascular disease. I have had the good fortune to be intimately involved with both discoveries. More importantly, many of the colleagues that I have interacted with in the process of doing this work have become life-long personal friends. To those with whom I have managed to combine scientific excitement with friendship I owe a double debt of gratitude.

Philos Trans R Soc Lond B Biol Sci. 2006 May 29; 361(1469): 735–759.
Published online 2006 February 8. doi:  10.1098/rstb.2005.1775
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English: Nobel laureate Dr. James D. Watson, C...

English: Nobel laureate Dr. James D. Watson, Chancellor, Cold Spring Harbor Laboratory. These images are freely available and may be used without special permission. (Photo credit: Wikipedia)

Novel Cancer Hypothesis Suggests Antioxidants Are Harmful

Reporter:

Larry H Bernstein, MD, FCAP

Hypothesis – following on James Watson

A new hypothesis that focuses on reactive oxygen species (ROS) proposes that antioxidant levels within cancer cells are a problem and are responsible for resistance to treatment.

The theory destroys any reason for taking antioxidative nutritional supplements, because they “more likely cause than prevent cancer,” according to Nobel laureate James Watson, PhD, from Cold Spring Harbor Laboratory, New York.

Dr. Watson, who shared the Nobel prize for unraveling the structure of DNA, regards this theory as being “among my most important work since the double helix, notes a press release from his institution, where he has been director since 1968.

The theory was published online January 8 in Open Biology.

Dr. Watson explains that

the vast majority of agents used to directly kill cancer cells, including

  • ionizing radiation,
  • most chemotherapeutic agents, and
  • some targeted therapies,

work by generating — either directly or indirectly — ROS that block key steps in the cell cycle.

This generation of ROS creates a hypoxic environment in which cancers cells undergo a transformation from epithelial to mesenchymal cells (EMT).

These transformed cells almost inevitably possess very high amounts of antioxidants, which effectively block the effects of anticancer treatments, Dr. Watson notes. Once a cancer becomes resistant to chemotherapy, it usually is equally resistant to ionizing radiation, he points out.

In addition, these transformed EMT cancer cells generate free-floating mesenchymal cells, which have the flexibility and movement that allows them to

  • metastasize to other body locations (brain, liver, lung).
  • “Only when they have moved do most cancers become life-threatening,” Dr. Watson notes.

Interestingly, the widely used antidiabetic drug metformin has been shown to preferentially kill mesenchymal stem cells. “In a still much unappreciated article published 3 years ago,

  • ” metformin added to chemotherapy
  • “induced prolonged remission if not real cures” in mouse models of cancer

(Cancer Res. 2009;69:7507-7511), Dr. Watson writes.

He notes that clinical trials are currently looking to see if adding

  • metformin to chemotherapy provides clinical benefits
  • diabetics who have been using metformin regularly have a reduced incidence of many cancers.

Resistance to Therapy From Antioxidants in Cancer Cells

Dr. Watson proposes that anticancer therapies work by generating ROS, which cause apoptosis.

However, as cancer cells evolve, they produce antioxidant proteins that block this effect, such as

  • glutathione,
  • superoxide dismutase,
  • catalase, and
  • thioredoxin.

The fact that cancer cells largely driven by RAS and Myc are among the most difficult of cancers to treat

  • could be due to their high levels of ROS-destroying antioxidants, Dr. Watson argues.
  • High antioxidative levels might also explain the effective incurability of pancreatic cancer, he adds.

If this theory is correct, then drugs that lower antioxidant levels within cancer cells would be therapeutic.

In fact, the ROS-generating agent arsenic trioxide has been shown to reduce levels of glutathione and thioredoxin. Arsenic trioxide is

  • currently being used to treat promyeloblastic leukemia, but this theory
  • suggests that the drug could be useful in many major cancers.

Nutritional Antioxidants Could Be Harmful

One far-reaching implication of this theory is that antioxidants as nutritional supplements, including

  • beta-carotene,
  • vitamins A, C, and E, and
  • selenium, could be harmful in cancer.

For years, such supplements have been widely hyped for cancer prevention and/or treatment, as has

  • encouragement to eat colorful fruit and berries, which contain antioxidants.

The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.

However, Dr. Watson warns that recent data strongly hint that much of the untreatability of late-stage cancer might be the result of “its possession of too many antioxidants, [so]

  • the time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.”

Many nutritional intervention trials have shown no obvious effectiveness in preventing gastrointestinal cancer or in lengthening mortality, he writes. “In fact, they seem to slightly shorten the lives of those who take them.”

Hence, he concludes, “blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.”

Very Complex Process

Maurie Markman, MD, national director for medical oncology at the Cancer Treatment Centers of America, who writes the Medscape Markman on Oncology blog, was asked to comment on the theory.

“The importance of the critical relationship between oxidating activity and antioxidants in the normal functioning of cells has been recognized by many investigators, and it is not surprising that this process would be quite relevant in cancer. However,

  • it must be emphasized that this is a very complex process and the balance between these powerful influences at the cellular level is certain to be very carefully controlled.
  • it should be noted that antioxidants are components of our normal diets.
  • it is most unlikely that a simple approach to somehow removing antioxidants from the body will be a useful strategy in cancer management,”

Open Biol. 2013;2:120144. Full text

Comment: Dr. Larry H. Bernstein

Pathology has a tradition going back to Rokitanski and Rudolph Virchow.  The complexity of this issue is that there is a concomitant metabolic abnormality. and a series of step-by-step changes in the cell related to a change from aerobic to anaerobic glycolysis in the presence of oxygen, noted by Otto Warburg, which is accompanied by mutations, which combined lead to cellular prolieration and cell migration.  When you reach the stage of metastasis to distant sites, the process most likely is irreversible.

The proposal that the epithelial cells become mesenchymal is not tenable in the case of most epithelial tumors, at least in the sense that they are not sarcomas.  The problem is that the intercellular adhesion breaks down, and the underlying stroma also is malignant.  If that is what is inferred, it is a new twist.

________________________________________________________________________________________________________________________________________________________________

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_________________________________________________________________________________________________________________________________________________________________

Blackberries are a source of polyphenol antiox...

Blackberries are a source of polyphenol antioxidants (Photo credit: Wikipedia)

Reactive oxygen species and detoxifying system...

Reactive oxygen species and detoxifying system (French) (Photo credit: Wikipedia)

English: Major cellular sources of ROS in livi...

English: Major cellular sources of ROS in living cells. Novo and Parola Fibrogenesis & Tissue Repair 2008 1:5 doi:10.1186/1755-1536-1-5 (Photo credit: Wikipedia)

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Reporters:

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN 

DNA pioneer James Watson takes aim at “Cancer establishments”

By Sharon Begley

Sharon Begley, the senior health & science correspondent at Reuters, was the science editor and the science columnist at Newsweek from 2007 to April 2011, and a contributing writer at the magazine and its website, The Daily Beast, until December 2011. From 2002 to 2007, she was the science columnist at The Wall Street Journal, and previous to that the science editor at Newsweek. She is the co-author (with Richard J. Davidson)  of the 2012 book The Emotional Life of Your Brain, the author of the 2007 book Train Your Mind, Change Your Brain, and the co-author (with Jeffrey Schwartz) of the 2002 book The Mind and the Brain. She is the recipient of numerous awards for her writing, including an honorary degree from the University of North Carolina for communicating science to the public, and the Public Understanding of Science Award from the San Francisco Exploratorium. She has spoken before many audiences on the topics of science writing, neuroplasticity, and science literacy, including at Yale University (her alma mater), the Society for Neuroscience, the American Association for the Advancement of Science, and the National Academy of Sciences.Follow me on Twitter: https://twitter.com/sxbegle for breaking science news, not what I’m having for breakfast.
  • On the $100 million U.S. project to determine the DNA changes that drive nine forms of cancer: It is “not likely to produce the truly breakthrough drugs that we now so desperately need,” Watson argued. On the idea that antioxidants such as those in colorful berries fight cancer: “The time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.”
  • The main reason drugs that target genetic glitches are not cures is that cancer cells have a work-around. If one biochemical pathway to growth and proliferation is blocked by a drug such as AstraZeneca‘s Iressa or Genentech’s Tarceva for non-small-cell lung cancer, said cancer biologist Robert Weinberg of MIT, the cancer cells activate a different, equally effective pathway.
  • That is why Watson advocates a different approach: targeting features that all cancer cells, especially those in metastatic cancers, have in common.
  • One such commonality is oxygen radicals. Those forms of oxygen rip apart other components of cells, such as DNA. That is why antioxidants, which have become near-ubiquitous additives in grocery foods from snack bars to soda, are thought to be healthful: they mop up damaging oxygen radicals.
  • That simple picture becomes more complicated, however, once cancer is present. Radiation therapy and many chemotherapies kill cancer cells by generating oxygen radicals, which trigger cell suicide. If a cancer patient is binging on berries and other antioxidants, it can actually keep therapies from working, Watson proposed.
  • “Everyone thought antioxidants were great,” he said. “But I’m saying they can prevent us from killing cancer cells.”
  • One elusive but promising target, Watson said, is a protein in cells called Myc. It controls more than 1,000 other molecules inside cells, including many involved in cancer. Studies suggest that turning off Myc causes cancer cells to self-destruct in a process called apoptosis.
  • “The notion that targeting Myc will cure cancer has been around for a long time,” said cancer biologist Hans-Guido Wendel of Sloan-Kettering. “Blocking production of Myc is an interesting line of investigation. I think there’s promise in that.”
  • Targeting Myc, however, has been a backwater of drug development. “Personalized medicine” that targets a patient’s specific cancer-causing mutation attracts the lion’s share of research dollars.
  • “The biggest obstacle” to a true war against cancer, Watson wrote, may be “the inherently conservative nature of today’s cancer research establishments.” As long as that’s so, “curing cancer will always be 10 or 20 years away.”(Reporting by Sharon Begley; Editing by Jilian Mincer and Peter Cooney)

SOURCE:

http://in.reuters.com/article/2013/01/09/usa-cancer-watson-idINDEE90804520130109

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