BOD L10 ISC & Cardioprotection pt3

Question 1

What role do kinases play in IPC?

Answer 1

Both pro-apoptotic and anti-apoptotic means they play both protective and damaging roles.

Question 2

What is delayed-IPC?

Answer 2

24-72 hours after preconditioning event, IPC is also observed.

Question 3

How does delayed-IPC differ fundementally from initial IPC?

Answer 3

Involves changes in protein expression

Question 4

What two ways does delayed-IPC work through?

Answer 4

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

Question 5

Which HSP’s are involved in delayed-IPC?

Answer 5

HSP-72 hallmark of this. Inhibits JNK.

HSP-27 binds cytochrome C, prevents release

HSP-70 binds Apaf1 prevents caspase 9 activation

Question 6

Which enzymes are involved in delayed-IPC?

Answer 6

Inducible nitric oxide synthase (iNOS) -
increases NO, which is cardioprotective.

Superoxide disumtase (SOD) - 
Decreases ROS

Cyclooxygenase-2 (COX-2) -
Decreases prostanoids which are cardioprotective

Question 7

What role do prostanoids play in delayed-IPC?

Answer 7

They are inflammatory, but protective

Generated by COX-2.

Question 8

What two enzymes are involved in NO synthesis, where are they found? What induces them?

Answer 8

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.

Question 9

Why is NO protective?

Answer 9

Inhibits Ca2+ influx, opens K-ATP channels, anti-oxidant.

Activates COX-2.

Anti-apoptotic effects.

Question 10

Why are prostanoids protective?

Answer 10

Inhibit Ca2+ influx.

Open K-ATP channels

Inhibit neutrophil infiltration.

Question 11

What two cardioprotective strategies are based on generating NO?

Answer 11

Nitroglycerin (NO donor)

iNOS gene therapy

Question 12

How does NO signal?

Answer 12

Activates guanyl cyclase, converts cGMP from GTP.

This activates PKG

Question 13

What two TFs cativated by protein kinases transcribe iNOS and COX genes?

Answer 13

NK-kB iNOS and COX.

STAT iNOS

Question 14

What role does ERK1/2 play in survival?

Answer 14

Pro survival, promotes proliferation and evasion of apoptosis.

ERK phosphorylates BAD and CREB, inhibiting them.

Phos. of BAD inhibits apoptotic activity.

Question 15

What role does protein kinase B (PKB) play in cell survival?

Answer 15

Also anti-apoptotic. Works in many cell types including cardiomyocytes.

Question 16

What is the mitochondrial permeability transition pore (MPTP)

Answer 16

Pore which opens the inner mitochondrial space to the cytoplasm.

Question 17

Where does the MPTP span?

Answer 17

Spans the outer and inner mitochondrial membranes.

Question 18

What are the consequences of the MPTP opening?

Answer 18

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

Question 19

How is the MPTP opened?

Answer 19

Calcium ions overload in cytoplasm.

Question 20

What role does MPTP opening play in perfusion injury?

Answer 20

During perfusion, conditions for MPTP opening are present.

mPTP opening occurs during myocardial reperfusion.

Inhibition of MPTP openning at reperfusion is cardioprotective.

Question 21

What is glycogen synthase kinase-3beta

Answer 21

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.

Question 22

What are future targets for treatment - summary slide.

Answer 22

Question 23

What is the most crucial strategy to limit infarct size?

Answer 23

Early reperfusion.

Done by angioplasty or thrombolytic therapy