lessons in science - european society of...
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Lessons in Science:
Competition In Scientific Research
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“Competition…. inclineth
to contention, enmity, and war”
Thomas Hobbes, Leviathan, 1651
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• Discovered in 1845
• A typical endothelial cell is about 30µm long,
10µm wide, and 0.2 – 3 µm thick
• Accounts for 1% or less of the arterial weight
• As recently as the late 1960s it was thought
of as merely “a sheet of cellophane”
Endothelium
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Prostacyclin and NO – fundamental mediatorsin the vasculature
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Bioassay profile of different vasoactive substances
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One great advantageof bioassay is that itmeasures biological
activity
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Snap CracklePop
HIF
MIF
Smac-Diablo
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Arachidonic acid
Prostaglandin F2α Prostaglandin E2
Metabolic pathway of arachidonic acid, 1971
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This explained the mechanismof action of aspirin-like drugs
…and at least one of their sideeffects _ the gastric damage
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Experiences with aspirin(acetyl salicylic acid) in the
nonspecific prophylaxis of coronary thrombosis
Craven (1953) Mississippi Valley Med. J. 75: 38 - 44
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Arachidonic acid
cyclic endoperoxidesPGG2, PGH2
thromboxane A2
Metabolic pathway of arachidonic acid, 1975
prostaglandin F2α
prostaglandin E2
prostaglandin D2 malondialdehyde MDA
C17 hydroxyacid
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Platelet aggregation induced by PGG2 and TXA2
PGG2500ng
PGG2250ng
PGG2100ng
TXA2extracted
From100ngPGG2
2 minOpticaldensity
Needleman et al, (1976) Nature 261: 558 - 560
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Arachidonic acid
cyclic endoperoxidesPGG2, PGH2
thromboxane A2
Metabolic pathway of arachidonic acid in platelets
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Is the vasoconstrictor
thromboxane A2 also
made by the vessel wall?
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Differential bioassay of PGE2 and vessel wall extract
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The birth of a discovery
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Arachidonic acid
cyclic endoperoxidesPGG2, PGH2
thromboxane A2prostacyclin
Metabolic pathway of arachidonic acidin platelets and the vessel wall
?
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Aspirin selectively inhibits platelets
• platelet cyclooxygenase is very sensitive
to aspirin*
• inhibition of platelet cyclooxygenase lasts
for the whole lifetime of the platelet
*Burch et al (1978) J. Clin. Invest. 61: 314-319
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Effect of low and high dose aspirin on bleeding time in healthy volunteers
O’Grady and Moncada (1978) Lancet 312:780
0123456789
Control 0.3 gaspirin
3.9 gaspirin
Ble
edin
g tim
e (m
in)
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Arachidonic acid
thromboxane A2cyclic endoperoxides
PGG2, PGH2prostacyclin
Effect of low - dose aspirin on the metabolic pathway of arachidonic acid in platelets and the vessel wall
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Clinical trials show that aspirin:
• prevents stroke in patients withatherosclerosis or TIA
• reduces risk of myocardial infarctionin unstable angina
• reduces mortality in acute myocardialinfarction
• prevents occlusion of vein grafts• reduces risk of metastasis in cancer patients
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Don’t use aspirinfor primary prevention
of cardiovascular disease
Barnett et al (2010) Brit. Med. J. 340: 920 - 922
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It will be difficult
to beat “old aspirin”
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Cyclooxygenases (1990)
COX-1: physiological processes
COX-2: inflammatory responses
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Inhibition of COX-2results in:
• inhibition of prostacyclin
• cardiovascular side effects
McAdam et al. (1999) Proc. Natl. Acad. Sci. USA 96: 272 - 277
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The maker of Vioxx has agreed to pay $4.85bn to settle legal claims that the controversial drug caused many users to suffer strokes and heart failure.
Vioxx was withdrawn from sale in 2004
Vioxx settlement to total $4.85bn
BBC News Channel, Monday March 12th 2007
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From: White (2007) Hypertension 49: 408-418
Cardiovascular risk of COX inhibitors
Drug
NaproxenMeloxicamIndomethacinIbuprofenDiclofenacRofecoxib (>25 mg)Rofecoxib (<25mg)Celecoxib
Relative risk vs nonuser
0.971.251.301.071.402.191.331.06
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Arachidonic acid
cyclic endoperoxidesPGG2, PGH2
thromboxane A2prostacyclin
Effect of a COX-2 inhibitor on the metabolic pathway of arachidonic acid in platelets and the vessel wall
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COX-2 inhibitors may be beneficial in:
• cancer – colon, breast, prostate, lung• Alzheimer’s disease• Parkinson’s disease• schizophrenia• major depression• ischaemic brain injury• diabetic peripheral nephropathy
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O
OH
HOOC
OH
Prostacyclin
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Clinical uses of prostacyclin:
• Primary pulmonary hypertension
• Peripheral arterial disease
• Cardiopulmonary bypass
• Organ transplantation
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The obligatory role of endothelium in ACh-inducedvascular relaxation
Furchgott and Zawadzki, Nature 288, 373-376, 1980
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Bioassay of EDRF released from endothelial cells
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Detection of endogenous and exogenous NO
Palmer et al (1987) Nature 327: 524 - 526
A Bioassay
B Chemiluminescence
Column
1 sec
RbA
GTN50nM
OT
3 10 30 100 0.07 0.22 0.67 GTN50nM
OT
3 10 30 100 0.07 0.22 0.67NO2-
0.7nmol
NO2-
0.7nmol
10 min
2 cm
Con
trac
ted
by U
4661
9 (3
0nM
)
10 min
Bk nM TC NO nmol
Bk nM TC NO nmol
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“You were very persuasive; butunconvincing! I am sceptical for thesimple reason that the formation of
nitrogen oxides demands somepretty heavy thermodynamic
considerations. Nitric oxide isproduced in the upper
atmosphere through the energicintervention of lightning!”
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O O2 N2H
L-citrulline
NH
2H N COOHNADPH
NO
2H N COOH
NHNH
HO HN HNHNN2H
2H N COOH
NADPH
Nω-hydroxy-L-arginineL-arginine
L-NMMAL-NMMA
The L-arginine:NO pathway
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L-arginine:NOpathway
Biology of the L-arginine: NO pathway
Cardiovascularsystem
Nervoussystem
Immunologyand
inflammation
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The action of nitric oxideIn the corpus cavernosum
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Effect of L-NMMA (100mg kg-1)on blood pressure and heart rate
Rees et al, (1989) Proc. Natl. Acad. Sci. USA 86: 3375 - 3378
L-NMMA100mg kg-1
L-NMMA100mg kg-1
L-arginine300mg kg-1
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The cardiovascularsystem is in a state
of activevasodilatation
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Nitric oxide inhibits
• Platelet aggregation
• Smooth muscle cellproliferation
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Lack of vascular nitric oxide
contributes to
hypertension, vasospasm
and atherosclerosis
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Endothelial dysfunction :predicts disease in patients with
a family history of essential hypertension or risk factors for atherosclerosis
Taddei et al (1996) Circulation 94: 1298 - 1303
Reddy et al (1994) J. Am. Coll. Cardiol. 23: 833 - 843
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Oxidative stress: a most
significant factor in
cardiovascular disease
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arachidonic acid
PGG2
prostacyclin synthase
prostacyclin
L-arginine
NO
O2-1976
1986
ONOO-
X
Oxidative stress, prostacyclin and NO
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Conditions in which ONOO- has been implicated
• atherosclerosis• hyperlipidaemia• hypertension• myocarditis• chronic renal failure• septic shock• diabetes• angiotensin II-mediated vascular disorders• cigarette smoking
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Where do the reactive oxygen speciescome from?
• NADPH oxidases
• xanthine oxidase
• uncoupled endothelial NO synthase
• mitochondrial electron transport
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Nitric oxide and the respiratory chain
succinate
NADH
INADH
dehydrogenase complex
IIsuccinate
dehydrogenasecomplex
IIIcytochromeb-c1 complex
IVcytochrome
oxidasecomplex
O2 NONOoO2-
oO2-
H2O2
SOD
Palacios - Callender et al (2004)Proc. Natl. Acad. Sci. USA 101: 7630-7635
Cleeter et al (1994) FEBS Letters 345: 50 - 54
Formation of ROS in the presence of NOFormation of peroxynitrite
ONOO-
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Hypotheses are nets:
Only he who casts will
catch (Novalis)
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The quality of the question
defines the quality of the project
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Questions
• discard most of them ruthlessly
• sharpen the remainder
• rank them
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and above all......
simplify them!
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AcknowledgementsJohn VaneSergio FerreiraVera PontieriArnold HermanStuart BuntingPhil NeedlemanRichard GryglewskiJohn SalmonGreg DustingKevin MullaneGerry HiggsBrendan WhittleRod FlowerKarsten SchrorAnnie HiggsJose-Luis AmezcuaGautam ChaudhuriFernando UbatubaJohn O’GradyMarek RadomskiMassimo Di Rosa
Takashi TeranoElisabetta DejanaGilberto De NucciRichard PalmerPatricio Lopez-JaramilloJuan EspluguesTherese McCallJohn GarthwaiteGiti GarthwaitePatrick VallanceTerry BennettSheila GardinerRichard KnowlesEddy LiewPeter WiklundLars GustafssonJose Ramon BerrazuetaMartin FeelischRick SchulzVictor Darley-UsmarMaria Angeles Moro
Guy BrownIan CharlesWeiming XuIgnacio LizasoainSelim CellekJorge ErusalimskyAngeles AlmeidaJuan BolanosJesus MateoCormac TaylorDaryl ReesNeale FoxwellMiriam PalaciosBelen BeltranEmilio ClementiAntonia OrsiThilo HagenVeronica HollisMarisol QuinteroSergio ColomboAssegid Garedew
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