BOD L10 ISC & Cardioprotection pt3 Flashcards
What role do kinases play in IPC?
Both pro-apoptotic and anti-apoptotic means they play both protective and damaging roles.
What is delayed-IPC?
24-72 hours after preconditioning event, IPC is also observed.
How does delayed-IPC differ fundementally from initial IPC?
Involves changes in protein expression
What two ways does delayed-IPC work through?
Heat shock proteins -
The HSP proteins when active, promote cell survival via inhibiton of apoptosis.
Enzymes -
various ways such as increasing NO, reducing ROS and increasing prostaoids
Which HSP’s are involved in delayed-IPC?
HSP-72 hallmark of this. Inhibits JNK.
HSP-27 binds cytochrome C, prevents release
HSP-70 binds Apaf1 prevents caspase 9 activation
Which enzymes are involved in delayed-IPC?
Inducible nitric oxide synthase (iNOS) -
increases NO, which is cardioprotective.
Superoxide disumtase (SOD) - Decreases ROS
Cyclooxygenase-2 (COX-2) -
Decreases prostanoids which are cardioprotective
What role do prostanoids play in delayed-IPC?
They are inflammatory, but protective
Generated by COX-2.
What two enzymes are involved in NO synthesis, where are they found? What induces them?
endothelial nitric oxide synthase (eNOS)
inducible nitric oxide synthase (iNOS)
eNOS found in heart cells. Induced by calcium ion overload during ischaemia.
iNOS induced by NO formed from eNOS - positive feedback.
Why is NO protective?
Inhibits Ca2+ influx, opens K-ATP channels, anti-oxidant.
Activates COX-2.
Anti-apoptotic effects.
Why are prostanoids protective?
Inhibit Ca2+ influx.
Open K-ATP channels
Inhibit neutrophil infiltration.
What two cardioprotective strategies are based on generating NO?
Nitroglycerin (NO donor)
iNOS gene therapy
How does NO signal?
Activates guanyl cyclase, converts cGMP from GTP.
This activates PKG
What two TFs cativated by protein kinases transcribe iNOS and COX genes?
NK-kB iNOS and COX.
STAT iNOS
What role does ERK1/2 play in survival?
Pro survival, promotes proliferation and evasion of apoptosis.
ERK phosphorylates BAD and CREB, inhibiting them.
Phos. of BAD inhibits apoptotic activity.
What role does protein kinase B (PKB) play in cell survival?
Also anti-apoptotic. Works in many cell types including cardiomyocytes.
What is the mitochondrial permeability transition pore (MPTP)
Pore which opens the inner mitochondrial space to the cytoplasm.
Where does the MPTP span?
Spans the outer and inner mitochondrial membranes.
What are the consequences of the MPTP opening?
Mitochondria swell, causing OMM rupture and release of cytochrome C involved in apoptosis.
Also can lead to necrotic cell death, acidification of IMM, decline in ATP production
How is the MPTP opened?
Calcium ions overload in cytoplasm.
What role does MPTP opening play in perfusion injury?
During perfusion, conditions for MPTP opening are present.
mPTP opening occurs during myocardial reperfusion.
Inhibition of MPTP openning at reperfusion is cardioprotective.
What is glycogen synthase kinase-3beta
Serine/threonine kinase involved in regulation of many processes. e.g. glucose metabolism and apoptosis.
Active when unphoshporylated.
Phosphorylation at Ser9 inhibits activity of protein kinase. This is anti-apoptotic.
What are future targets for treatment - summary slide.
What is the most crucial strategy to limit infarct size?
Early reperfusion.
Done by angioplasty or thrombolytic therapy
