Metabolic Response To Ischemia And Reperfusion

Question 1

Why is oxygen needed in tissues

Answer 1

Used in CAC to break down acetyl groups and generate free hydrogen atoms

Also used as the final except of hydrogen atoms in the ETC to generate H2O
- generates ATP for cells

Question 2

Primary cardiac fuel courses

Answer 2

FAs are the number 1

Can also use:

• ketone bodies
• glucose
• lactate acid

ALL 4 generate acetyl CoA for CAC

Question 3

How much ATP is generated by 1 FA?

Answer 3

32 ATP.

- this is the most of any substrate, hence why cardiac cells use this the most as long as its available

Question 4

What happens in hypoxic conditions in cardiac cells?

Answer 4

1) CTC shuts down because of overproduction of NADH and FADH2 since the ETC cant accept any (also no FAD+ and HAD+ substrates are being recycled)
2) ETC shuts down due to over production of H ions that cant be removed due to no Oxygen end acceptor.

Because of 1 and 2, cardiac cells will undergo anaerobic glycolysis using glucose
- this causes a build up lactate which generates 2 ATP (lack of energy) per glucose and also decrease pH (acidic conditions)

leads to cell death

Question 5

Does gluconeogenesis occur in cardiac tissue?

Answer 5

NO

Only liver and some muscle cells

Question 6

Consequences of reperfusion to an ischemic area

Answer 6

The ETC oxygen flow changes

• coenzyme Q in ETC starts accepting oxygen and binds it with hydrogen to produce superoxide anions
• the superoxide anions form hydrogen peroxide and eventually free hydroxyl radicals
• (all three are free radical damage)*

Results in:

• lipid peroxidation
• membrane damage
• cell death

Question 7

Superoxide dismutase(SOD) and catalase

Answer 7

SOD: Enzyme that catalyzes dismutation of a superoxide anions into either normal oxygen or hydrogen peroxide

Catalase: enzyme that catalyzes hydrogen peroxide into water

both are used in conjunction as the antioxidant defense system to protect against ROS damage

These enzymes tries to counterbalance perfusion but cant in most cases

Question 8

Acute myocardial ischemia reperfusion (IRI)

Answer 8

Arises in patients who have a STEMI or acute MI who were treated effectively for their MI, but really quickly

• the MI damage and hypoxia is repaired, however reperfusion occurs to quickly causing cellular damage due to overproduction of ROS in wonky ETCs

Question 9

Difference in ischemia and reperfusion damage to cardiac cells

Answer 9

Ischemia: causes increased calcium and sodium ions intracellularly
-however the lowered pH as a result from anaerobic respiration prevents the Mitochondrial permeability transition pore (MPTP) from opening which inhibits myofibril function even though intracellular calcium is high

Reperfusion: normal ion and mitochondrial action is restored, however ETC overproduces ROS due to wonky/damaged channels and the increase intracellular calcium. Causes MPTPs to remain open and the ROS can damage mitochondria DNA, produce lipid peroxidation and enzyme denaturation of cellular membranes (dissolves them) and can intitate apoptosis of cells.

• also causes seizing of myofibrils due to increased intracellular calcium and overrelease of calcium from the damaged SRs

Question 10

Clinical tests for MI

Answer 10

Troponin levels:

• regulatory proteins involved in muscle contractility. The cardiac specific (cTn) is used in cardiac cells specifically
• high levels in blood indicate MI damage (4-6 hrs w/ peak of 50x normal amount)
• high cTn levels is the gold standard for MI*

Creatine kinase (type 2 specifically CK-MB)

• helps speed up ADP->ATP conversion at myofibrils which helps produce ATP efficiently
• high levels in blood indicate MI (4-8 hrs w/ peak of 4x the normal amount)

Question 11

3 types of creatine kinase

Answer 11

CK1 (CK-BB): brain creatine kinase ONLY

CK2 (CK-MB): cardiac and skeletal muscle creatine kinase

CK3 (CK-MM): skeletal muscle creatine kinase ONLY

Question 12

Remote ischemic conditioning to reduce reperfusion injury

Answer 12

Remote ischemic conditioning:

• experimental; procedure that repeatedly temporally blocks off blood flow to a limb
• this is suppose to help activate the body’s natural protective physiology against ROS species and reperfusion injury
• similar to repeatedly getting small doses of poison from bites in order for you to build resistance to the real deal if it happens*

Question 13

What does treating MIs w/reperfusion do to troponin and CK-MB levels compared to non reperfusion

Answer 13

Reperfusion:

• more short term damage w/ less long term damage
• CK-MB and troponin levels will peak very high but taper off to normal levels quicker

No reperfusion:

• less short term damage but the damage state persists
• CK-MB and troponin levels will peak, but not as high as reperfusion. However the levels take longer to level out to normal

Question 14

Types of troponin

Answer 14

TnT: troponin T that binds to tropomyosin and helps position it to actin, allowing muscles to relax when they actually relax

TnI: troponin I that binds to actin in thin myofilaments to help stabilize the reaction
- also prevents myosin from binding to actin in relaxed muscles

cTn: cardiac troponin that binds to cardiac specific myofilaments and allows better contractility
- hallmark measurement for MIs/ cardiac ischemia