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Cardiovascular Pathobiology And Treatment > Eicosanoid Mediators > Flashcards

Eicosanoid Mediators Flashcards

1
Q

Mediators derived from phospholipids include:

A

Eicosanoids
-prostanoids : prostaglandins (PG) thromboxanes - TX
-leukotrienes (found in leukocytes) LT
-lipoxins
-resolvins
Platelet activating factor PAF
-formed by acetylation of lyso-phospholipid

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2
Q

Describe platelet activating factor

A

Activates GPCR/cyclic AMP
Vascular permeability, wheal formation
Promotes TXA2 synthesis in platelets
Hyperalgesia at higher doses
Chemotaxin for neutrophils and monocytes

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3
Q

Describe eicosanoids

A

Derived from polyunsaturated fatty acids containing more than or equal to 3 C=C bonds eg arachidonic acid - usually esterified in phospholipids
Generally de novo as required and released from cells by a carrier-dependent mechanism
Local hormones with short-lived action
Important mediators/modulators of inflammation

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4
Q

Describe the structure of prostaglandin

A

Eicosanoids
20 C fatty acid containing 5 carbon ring
Series of PGs generated due to isomerases/reductases
Subscript indicates number of C=C outside the ring
A/b orientation of OH above/below plane of ring

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5
Q

Describe the action of phospholipases in initiating eicosanoid synthesis

A

Initial rate limiting step: liberation of arachidonate
Main substrates PC, PE phospholipids, one (or 2) step enzymatic process, phospholipase A2

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6
Q

Describe phospholipase A2

A

> 40 isoenzyes identified
Membrane-associated, extrinsic or cystolic
Optimally active at neutral/alkaline pH
Differ in regard to
-substrate specificity, Ca2+ requirement, lipid modifications/membrane anchoring, sub-cellular localisation

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7
Q

Phospholipase a2 differential regulation by…

A

Transcription
Proteolytic cleavage of pro-enzyme
Reversible activation by ca2+
Receptors (Bradykinin) linked to stimulators/inhibitory G-proteins/second messengers
PLA2 activating proteins (PLAPs)
-similar to mellitin; regulate activity of subset of membrane-associated PLA2 enzymes

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8
Q

What stimuli liberate arachidonate from phospholipid molecule

A

Antigen-antibody interactions in mast cells
Thrombin in platelets
Complement component C5a in neutrophils
Bradykinin in fibroblasts

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9
Q

Where is cyclooxygenase

A

Compartmentalised in endoplasmic reticulum lumen
- other cellular process compete for free AA or impede AA interaction with enzyme
-formation of damaging radicals?

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10
Q

Describe the 2 enzymatic activities of cyclooxygenase

A

-endoperoxide synthase oxygenates AA followed by cyclisation to unstable cyclic endoperoxide PGG2
-peroxidase converts unstable PGG2 to another endoperoxide, PGH2 by reduction of 14 hydroperoxy group

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11
Q

Self-catalysed activation of cyclooxygenase

A

PGG2 serves dual function:
-activator of endoperoxide synthase activity <0.8um
-substrate for peroxidase activity (>0.8um)

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12
Q

Self catalysed inactivation of cyclooxygenase

A

Each COX enzyme produces finite amount of product (suicide sbstrates)
-radicals formed during reeducation of PHH2 attack susceptible amin acid on enzyme?
-limits daily production of PGs under physiological conditions?

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13
Q

Describe COX-1

A

Mainly constitutive, in most cells, generates ‘good’ PGs involved in normal homeostasis

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14
Q

Describe COX-2

A

Mostly nducible by cytokines, growth factors etc
Mainly found in inflammatory cells, generates ‘bad’ PGs involved in inflammation, disease pathogenesis

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15
Q

COX-3 is a…

A

Splice variant of COX-1 found in heart and CNS

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16
Q

COX isoforms differ in…

A

Substrate affinity, specificity, activation kinetics?

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17
Q

SNPs in COX-1 and COX-2 influence….

A

Individual susceptibility to disease, drugs?

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18
Q

Subsequent conversion depends on…

A

Relative expression of enzymes in each cell type
Diagram ()

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19
Q

Describe the pharmacological classification of prostanoid receptors

A

Distinc GPCR for each prostanoid
4 types of EP, 2 subtypes of DP, slice variants of FP and TP
Based on:
-opposing actions
-rank order of potency

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20
Q

Receptor-dependent actions of prostanoids relating to cardiovascular system

A

DP vasodilation, reduced platelet aggregation
IP vasodilation, reduced platelet aggregation, cardioprotection, natriuretic
FP increased ocular blood flow, heart muscle cell hypertrophy
TP vasoconstriction, platelet adhesion and aggregation, smooth muscle hyperplasia, angiogenesis

21
Q

EP1 receptor-dependent actions

A

Vasoconstriction

22
Q

EP2 receptor-dependent actions

A

Vasodilation, natriuresis

23
Q

EP3 receptor-dependent actions

A

vasoconstriction, reduced autonomic NT release

24
Q

EP4 receptor-dependent actions

A

Closure of ductus arteries is, maintenance of gastric mucosal blood flow, heart muscle cell hypertrophy, preserves micro circulation, constrains myocardial Ischaemia-repercussion injury

25
PGs released from…
Areas of inflammation Acute: local tissues, BVs, mast cells Chronic: monocytes and macrophages
26
Pro-inflammatory actions of prostanoids
• ↑↑ vasodilatation of pre-capillary arterioles – to increase blood flow to areas of acute inflammation • potentiate action of histamine, bradykinin on post-capillary venules • synergism with other inflammatory mediators, oedema
27
Anti-inflammatory actions of prostanoids
• decr lyosomal enzyme release • decr generation of toxic oxygen metabolites in neutrophils • decr histamine release from mast cells • decr activation of macrophages and lymphocytes • decr cytokine release
28
Role of prostanoids in pain, pyrexia
Do not produce pain but enhance bradykinin by sensitising afferent C fibres -predominant PGE2 EP1/EP2 involvement? -lower Na channel activation threshold Pyretic action, mediate fever in response to IL-1? -incr vascular COX-2/PGE synthase -PGE2 crosses blood brain barrier, acts on EP3 receptors on the thermosensitive neurons
29
Anti-inflammatory action of glucocorticoids due to ………… of ………
Indirect inhibition Of phospholipase A2
30
What are lipocortins
Membrane-associated proteins similar to cytoskeletal calpactins Compete with PLA2 for binding to phospholipid? (De) phosphorylation of lipocortins (PKC, PKA, TK) important in short-term regulation of PG synthesis
31
Inhibitors of PGH2 synthase (COX )
Non Steroidal Anti-Inflammatory Drugs Eg salicylates (aspirin) profens(ibuprofen)
32
Describe NSAIDS
Antipyretic, analgesic, anti-inflammatory effects > effective in mild/moderate pain of inflammatory origin rather than actuate/severe pain Aspirin, NSAIDs eg ibuprofen for peripheral analgesia - lower activation of sodium channels - COX-1 derivedPGs sensitise sensory neurons (EP1) - COX-2 derived PGs incr pain perception in spinal cord (EP2)
33
How would NSAIDs decr headache pain
Relieve headache pain due to decreasing vasodilator effects of PGs on cerebral vasculature? COX-2 (hypothalamic B.V. endothelium) implicated in pyrexia of infection COX-1 (sensory neurons) normal thermal regulation ?
34
Explanation for peptic ulcers induced by NSAIDs
• COX-1 (and COX-2?) derived PGs (E2, I2) important for – maintenance of gastric mucosal blood flow (EP2, EP4, IP) – ↑mucus (EP4), ↑ bicarbonate (EP1) ↓ acid secretion (EP3, IP) – ↓neutrophil activation/adhesion to vascular endothelium • COX-2 induced by irritants to enhance mucosal defence
35
GAstrointestinal side-effects of NSAIDs
• most NSAIDS cause some erosion of gastric mucosa –even enteric-coated formulations and iv administration confer some risk (indirect action on mucosa?) –attenuated TXA2 synthesis increases bleeding risk • inhibition of both COX-1 and COX-2 necessary for gastrointestinal toxicity? • NSAIDS delay ulcer healing? – COX-2 derived PGs (EP4) contribute to repair/healing of mucosa, ↑ epithelial restitution
36
What are the main PGs in the kidney
PGE2 and PGI2
37
Describe COX-1 and COX-2 in the renal system
• COX-1 (and COX-2) derived PGs influence renal perfusion – dilate renal afferent arteriole to ↑ RBF and ↑GFR [IP, EP2, EP4] (works with AngII which constricts efferent arteriole) – influence ↑under pathophysiological conditions – regulate renin secretion from juxtaglomerular apparatus •COX-2 derived PGs influence renal tubular Na+ balance – natriuresis, diuresis
38
Renal toxicity of NSAIDs associated with increased risk of…
Renal ischameia/failure especially in compromised patients Na+/fluid retention - espially in chronic heart failure/renal insufficiency Raised BP, incidence and severity of hypertension - lowered efficacy of diuretics, ACEIs, ARBs (not CCBs) - incr cardiovascular morbidity, mortality
39
State and explain COX-2 selective inhibitors
Coxibs eg rofecoxib, celecoxib Retain analgesic, anti-inflammatory and antipyretic effects Decr gastrointestinal toxicity/bleeding (CLASS, VIGOR) but no reduction in renal toxicity Preference of COX-2 vs COX1 for coxibs = 30-300 fold
40
Why was rofecoxib recalled?
Increased risk of thromboembolism (2004)
41
Describe pro-atherothrombotic effects of COXIBs
Increased risk of MI, sudden cardiac death and stroke - especially in pre-existing vascular disease, class effect rather than drug specific? Higher CV risk outfights lower gastrointestinal risk? -NSAID + gastrointestinal-protectant better to prevent gastric bleed than COXIB for patient at greater CV risk - do conventional NSAIDs with preference for COX-2 carry greater risk vs raproxen
42
Describe Coxib’s pro-atherothrombotic mechanism?
• TXA2 production by platelet (COX-1) not ↓ by coxibs • PGI2 production by endothelium ↓ (mainly COX-2?) (also loss of cardio-protective effect of PGI2 against myocardial ischemia-reperfusion injury?) –platelet cannot synthesise more COX-1 enzyme ↓TXA2 –endothelium spared /recovers ability to synthesise PGI2, –↓ thrombotic risk Contrast with low dose aspirin (COX-1 >>COX-2) coxibs for post-operative pain, dental extraction↓ bleeding tendency as spare TX?
43
Mechanism to explain increased CV risk?
• PGI2 is the predominant AA metabolite produced by endothelial cells • PGI2 synthesis by EC is largely via COX-2 • PGI2 acts with IP receptors on platelets and VSMC • IP activation inhibits platelet aggregation in response to TXA2, inhibits VSMC proliferation and migration, and promotes VSMC differentiation and vasodilatation
44
Cardiovascular uses for prostanoid analogues
• alprostadil (PGE1) ‒ patency of ductus arteriosus prior to surgery for congenital cardiac malformation • epoprostenol (PGI2) ‒ reduces platelet aggregation during haemodialysis (if heparin contra-indicated) • epoprostenol (intravenous infusion) or iloprost (PGI2 analog, inhalation) ‒ primary pulmonary hypertension
45
5-Lipoxygenase (5-LOX) pathway
Abundant in ling, platelets, mast cells, leukocytes Cytosolic enzyme associates with (nuclear envelope) membrane on calcium dependent activation 5-LOX activating protein (FLAP) necessary for channeling AA into LT synthesis in intact cells
46
BLT (LTB4) receptors : selective ligands, signal transduction, actions
Selective ligands: LTB4 (agonist); LTC4, D4 inactive amelubant (antagonist) Signal transduction: Gq/11Gi increase IP3/DAG; Gi decr cAMP Actions: chrmotaxis with neutrophils and macrophages, host anti microbial defence; release of toxic oxygen products; synthesis of adhesion molecules; cell proliferation, cytokine release (macrophages, lymphocytes); smooth muscle hyperplasia
47
What are cysteinyl continuing LTs
Potent spasmogens of bronchiolar muscle - LTE4 less potent, longer-lasting than LTC4, LTD4
48
Actions of cysteinyl containing LTs
• eosinophil adhesion, activation • airway smooth muscle hyperplasia/chronic remodelling • increase mucus secretion, nasal blood flow • local vascular permeability, wheal and flare response • remodelling / pathogenesis in atherosclerosis? • constrict small coronary resistance vessels • inflammatory response during I-R injury
49
CystLT2 leaders to
Atherosclerosis? Myocardial and cerebral I-R injury? Vascular remodelling after angioplasty

Cardiovascular Pathobiology And Treatment (13 decks)

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