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Cardiovascular Biology 311 > Lecture 6: Cardiac Metabolic Stress > Flashcards

Lecture 6: Cardiac Metabolic Stress Flashcards

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1
Q

Metabolic stress can be categorised into:

A

Acute (ischemia)

Chronic (diabetes)

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2
Q

How important is ATP production for the heart?

A

Essential, needed 24/7 as the heart never stops intentionally.

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3
Q

How is ATP produced?

A

Aerobically (normal)

Anaerobically (lactate is a bi-product)

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4
Q

What are the substrates for ATP production?

A

Normally 60-70% FA

~ 30% carbs

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5
Q

What pathways are used in aerobic ATP production?

A

CAC

ETC

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6
Q

What pathway provide most ATP?

A

95% ATP is from ETC in mitochondria

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7
Q

Write some short notes on the CAC

A
  • Pyruvate enters the mitochondria and is a substrate for the CAC
  • The CAC produces ATP, NADPH and FADH2 for ETC
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8
Q

write some short notes on the ETC

A
  • NADH and FADH2 produced by the CAC is used in the ETC at complex 1
  • A transmembrane charge is set up (via transport of H ions at complex 1 to 4) which is then utilised to generate ATP at complex 5.
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9
Q

What are the determinate of oxygen supply to myocytes?

A

Diastolic pressure
Coronary Resistance
O2 carrying capacity

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10
Q

What is diastolic resistance in determining oxygen supply?

A

Diastolic Resistance:

  • Coronary flow max in diastolic period
  • Aortic diastolic pressure determines coronary perfusion (60mmHg normally) (coronary ostea)
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11
Q

What is coronary resistance in determining oxygen supply?

A
  • Increased by vessel compression (max in systole)
  • Vascular tone (auto regulation)
  • Vessel Ostruction
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12
Q

What is O2 carrying capacity in determining oxygen supply?

A
  • Depends on the Hb level and O2 saturation (Stable)

- Usually max O2 extraction in the heart

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13
Q

What are the pathways for anaerobic metabolism?

A

Glycolysis

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14
Q

Write some short notes on glycolysis

A
  • Glucose yields net 2 ATP though glycolysis
  • Glycogen yields net 3 ATP through glycolysis (glyconeogensis)
  • Moderate kinetics
  • Moderate extent
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15
Q

What is the real function of CAC?

A
  • Fuels i.e acetyl CoA found in the cytosol, produce very little ATP through CAC.
  • Most ATP from ETC
  • Products of CAC create ETC transmembrane charge for the flow of ions and huge ATP generation
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16
Q

Describe how the cardiomyocyte obtains fuels for energy production:

A
  • Glucose obtained via GLUT 1 & 4

- FA transported via translocase and goes straight to mitochondria for entry into the CAC.

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17
Q

What happens to glucose once it enters the myocyte?

A

It undergoes glycolysis and its metabolites enter the CAC

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18
Q

What regulates glucose entry into the cells?

A

Insulin regulates glucose entry by altering the expression of GLUT 4.

However Glut 1 is always present

(this is important in chronic metabolic stress caused in diabetes)

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19
Q

What is ATP essential for?

A

Sliding filament theory and SERCA operation (its a Ca ATPase)

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20
Q

Describe the important signalling pathway of insulin;

A
  • Insulin (binds insulin receptor) and activates PI3K and AKT
  • AKT causes GLUT 4 insertion into the membrane and activates mTOR
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21
Q

What is the function of mTOR?

A

mTOR leads to;

  • Inhibition of autophagy
  • Activation of protein synthesis (involved in hypertrophy pathway)
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22
Q

What can the ration of AMP/ATP lead to the activation of?

A

AMPK is activated when the ratio of AMP/ATP is high i.e High AMP and low ATP

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23
Q

What does AMPK do once activated?

A

AMPK

  • Inhibits FA oxidation
  • Activates (regulates) glycolysis (observed in disease states)
  • Activates Autophagy
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24
Q

What are some types of metabolic stress on the heart?

A

Oxidative stress

Activation of autophagy

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25
Q

What is oxidative stress;

A

The imbalance between ROS and antioxidants.

ROS then are free to cause damage.

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26
Q

What does too much ROS lead to?

A

Too much ROS lead to ROS oxidising proteins and changing their structure

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27
Q

What is a major source of ROS?

A

NADPH Oxidase (enzyme) produces/ is an important source of superoxide.

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28
Q

How many steps are their in autophagy?

A

Five

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29
Q

What are the first two steps in autophagy activation?

A

1) Membrane buds off the ER

2) Initial proteins from membrane but extend that section of membrane and recruit additional proteins in to it.

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30
Q

What is the third step in autophagy activation?

A

ATTG8 is an important protein that binds to the cargo via an adaptive protein

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31
Q

What is the fourth step in autophagy activation?

A

The adaptive protein goes out and binds to the dysfunctional organelle/ protein. Where it binds and brings it back to ATTG8

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32
Q

Whats the fifth step in autophagy activation?

A

ATTG8 and adaptor protein and cargo binds to lysosome and is degraded.

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33
Q

Does autophagy degrade healthy proteins?

A

They also degrade healthy proteins for its amino acids to create new proteins when requested (not bad)

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34
Q

What can too much autophagy lead to?

A

Too much autophagy can lead to to lack of cell integrity and lead to cell death.

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35
Q

How are the sub types of autophagy defined?

A

Seperate pathways depending on what is being degraded i.e

  • Macrophage (macromolecules)
  • Mitophagy (mitochondria)
  • Glycophagy (Glycogen)
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36
Q

What are the types of metabolic challenges for the heart?

A

Acute or chronic

37
Q

What are some examples of acute metabolic stress?

A
  • Hypoxia (ischemia)
  • Sympathetic stimulation
  • Nutrient withdrawal (fasting)
  • Arrhythmias
38
Q

What are some examples of chronic metabolic stress?

A
  • Diabetes and insulin resistance
  • Heart failure
  • Chronic ischemia heart disease
  • Hypertension
39
Q

What example of acute metabolic stress is looked at?

A

Ischemia

40
Q

What is schema?

A

An imbalance between oxygen supply and demand.

Defined as: Coronary flow is inadequate to maintain steady-state metabolism.

Doesn’t need to be fully blocked

41
Q

What causes 90% of MI?

A

90% MI are caused by occur due to plaque rupture leading to thrombosis formation

42
Q

How does MI pain present?

A

MI pain is similar to angina, persists with rest. (25% no pain)

Angina normally goes away with rest.

43
Q

How is MI diagnosed using serum analysis?

A

Serum analysis detects intracellular molecules including;

  • (Creatine Kinase, TnT, Tnl)
  • Onset 4-8hrs
  • Peak 24 hrs
  • Baseline 48-72hrs
44
Q

How does ischemia affect excitation coupling in the myocyte?

A
  • An ischemic myocyte has low O2 therefore ATP production decreases.
  • Low ATP leads to loss of SERCA, sarcolemma Ca ATPase and Na/K ATPase
  • Anaerobic glycolysis occurs and its bi-products i.e lactic acid = H which decreases pH. (cellular acidosis)
45
Q

How does cellular acidosis affect excitation contraction coupling?

A
  • When H builds up the Na/H exchanger tries to remove H, thus Na builds up
  • However eventually H equilibrates between ICF,ECF
  • Excessive Na is removed by NCX which reverses.
  • This leads to Ca build up
46
Q

In summery, what happens to ionic distribution in myocyte ischemic insult.

A
  • Ca overload
  • Na overload
  • Cellular acidosis

Thus leading mechanisms of myocyte death

47
Q

What are the two pathways of myocyte death from myocardial hypoxia?

A
  • Disruptive ionic distribution death pathway

or

  • Cellular acidosis pathway
48
Q

Describe the ion distribution disruption in a myocardial hypoxia insult;

A

Myocardial hypoxia

  • Increased Na/H exchanger activity
  • Decreased ATPase activity
  • NCX reverses
  • Decreased SR Ca release.

Leading to

  • Ca overload
  • High ECF K
  • Na overload
49
Q

What does a disruption in ionic distribution lead to?

A
  • Ca overload
  • High ECF K
  • Na overload

Leads to;

  • Lipase and protease activation. = cell death

or

  • Altered resting membrane potential = Arrhythmias
50
Q

Describe what occurs in cellular acidosis as a result of myocardial hypoxia;

A

Myocardial hypoxia;

  • increased anaerobic metabolism
  • Decreased cell pH (lactic acid)
    Cellular acidosis
  • Chromatin clamping and protein denaturation

results in cell death

51
Q

Look at the diagram

A

in your notes

52
Q

Describe cellular events within an hour of MI

A

1-2 mins, Decreased ATP, Stops contraction
10 mins @ 50% ATP, Cell swelling, Decreased Resting Membrane potential, Arrhythmias
20-24mins Irreversible cell injury.

53
Q

What happens between 1-24 hrs of MI in terms of cellular events?

A

1-3hrs Interstitial oedema and disruption
4-12hrs Neutrophil infiltration
18-24hrs Start necrotic process (phagocytosis onset)

54
Q

What happens 2-4 days (early events) post MI in terms of cellular events?

A

Extensive phagocytosis of myocytes, fibroblasts (replace myocytes with dead collagen) and Connective tissue.

55
Q

What are the late events post MI?

A

5-7 days; Restoration of dead tissue
1 week; Thinning and dilation of infarct zones, myocyte slippage.
7 weeks; Fibrosis and scarring complete.

(dilation because dead cells cannot produce tension)

56
Q

What happens post ischemia that is vital?

A

post ischemia reperfusion

57
Q

Why is post ischemia reperfusion vital?

A

Post ischemia reperfusion is a vital interventaiton to re-instate blood flow to the heart and restore oxygen availability

58
Q

Can post ischemia reperfusion be bad?

A

Reperfusion can further increase heart dysfunction and cell death.

= Reperfusion injury

59
Q

What affect does reperfusion have on excitation coupling?

A

Reperfusion results in the restoration of oxygen and thus ATP production.

  • Ca ATPase active
  • SERCA active
  • External H is returned to normal.
60
Q

What happens to metabolic processes in reperfusion?

A

Metabolic processes wont immediately come back online - will be inefficient, lots of ROS b/c everything is inefficient.

61
Q

In reperfusion what happens when the external H is reduced?

A

The loss of external H causes a concentration gradient and H leaves the cell down this via the Na/H exchanger this causes Na overload in the cell

The result of this is reversed NCX goes into overdrive now causing Ca overload in early reperfusion.

62
Q

What does Ca overload in early reperfusion lead to?

A
  • Contracile dysfunction (myocyte cant relax)
  • Fatal arrhythmias
  • cardiomyocyte death
63
Q

What contributes to cellular events in ischemia-reperfusion?

A

Metabolic signalling pathways

64
Q

Describe the contribution of metabolic signalling pathways to ischemia;

A

Increase in AMP/ATP ratio thus leading to AMPK activation.

AMPK activation causes;

  • Decreased FA oxidation
  • Increased glycolysis (anaerobic)
  • Increased autophagy
65
Q

What else drives the increase in autophagy during ischemia?

A

increased autophagy is also driven by the decrease in mTOR concentration in an ischemic environment.

66
Q

What happens to the metabolic signalling pathways in reperfusion?

A
  • Autophagy decreases slightly (possibly)
  • ATP levels rise slightly
  • AMPK activity decreases slightly.
  • mTOR increases slightly (possibly)
  • ROS levels increase
67
Q

Why dont metabolic signalling pathways return immediately to normal with reperfusion?

A

None of these signalling levels return to normal levels because restoration is a gradual task and does not occur instant with reperfusion

68
Q

Whats an example of chronic metabolic stress?

A

Diabetes

69
Q

Is diabetes metabolic stress impacting only on the heart?

A

No, it is a systemic metabolic distrubance

70
Q

How does diabetes metabolically impact the heart?

A
  • High glucose
  • Low insulin (T1D) or high insulin (T2D)
  • High free FA, triglycerides
  • High fructose.
71
Q

How does diabetes affect myocytes at a cellular level?

A
  • Low glucose uptake
  • Increased FFA
  • Low glycolysis
  • Increased ROS = oxidative stress
72
Q

Describe how type 2 diabetes affects metabolic signalling

A

T2D; Impaired insulin resistance

Therefore less insulin/impaired

  • Less glut 4 into membrane
  • B/C AKT activity is decreased.
73
Q

In type 2 diabetes what does lowered AKT activity also lead to?

A

Lowered AKT activity also results in a decrease in glyocogen synthesis which is meadiated by the insulin-AKT pathway

74
Q

How does the heart respond to low glucose and insulin resistance?

A

The heart responds by increasing glycogen storage (GLUT 1 always present)

It is unknown how this occurs and its consequences

75
Q

What can activate glycogen phosphorylase in a myocyte?

A

The b adrenergic pathway

76
Q

How does the heart store glyocogen?

A

In both alpha and beta strucutral forms suggesting slow vs rapid release.

This is different from elsewhere in the body.

77
Q

Whats another consequence of diabetes in the heart?

A

Protein glycation

78
Q

What is protein glycation?

A

Glucose binds to proteins and form amadori products.

Over weeks/months amadori products become Advanced Glycation End Products (AGE’s) this is irrversible and modify protein function (very damaging)

79
Q

In diabetes how else do AGEs effect the heart?

A
  • Collagen cross linking AGE’s are evident, contributing to ventricular stiffness.
  • Evidence there is glycation of SERCA and RYR in rat cardiomyocytes.
80
Q

In diabetes what is form of metabolic stress?

A

Fructose toxicity

81
Q

How are fructose levels high in diabetes?

A
  • There is increased fructose by 30% over 30 years in parallel with increased insulin resistance.
  • Increasing plasma fructose and cellular exposure.
82
Q

Describe fructose metabolism

A

Not well regulated

83
Q

Experimentally what does high dietary fructose lead to?

A
  • Insulin resistance and diabetes
84
Q

How does fructose create metabolic stress?

A
  • It has the potential to bypass phosfructokinase regulation of glycolysis
  • Enters the hexosamine biosynthesis pathway to produce o-glcNaCylation (reversible signalling regulatory modification of proteins)
85
Q

What transports fructose into the cell?

A

Glut 5 only transports fructose and is present in myocardiocytes

86
Q

In fructose dietary experiments, what was found?

A

Fructose did no produce
- Hypertension or obesity

Thus does not cause pressure or volume overload.

But did cause
- Insulin resistance and mild hyperglycemia

87
Q

whats the cardiac morphology of high fructose?

A
  • No change in heart size
  • Increased interstitial fibrosis in the myocardium, myocyte loss ~4%
  • Activated autophagy in fructose fed mouse hearts.
  • increased oxidative stress (increased superoxide production)
88
Q

How does the mouse experiments translate into human implications for the diabetes, fructose toxicity?

A

Bad implications for humans as the exposure to raised fructose or protein glycation etc can be over a much larger time scale.

Cardiovascular Biology 311 (18 decks)

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