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Cardio Week 2 > Lecture 22: Alterations in Myocardial Metabolism > Flashcards

Lecture 22: Alterations in Myocardial Metabolism Flashcards

(49 cards)

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1
Q

What is ischemia?

A

A temporary lack of blood supply in a tissue or organ

Dependent on metabolic activity

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2
Q

What is hypoxia?

A

A temporary lack of oxygen concentration in a tissue or organ
Substrate removal from tissue is still normal
Not the same as anoxia

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3
Q

What is hypoxic-hypoxia?

A

When arterial oxygen content is below normal but there is adequate blood flow to deliver glucose and remove lactate
Different from ischemia

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4
Q

Why does heart use so much oxygen during rest and exercise?

A

High mitochondrial content (30%)

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5
Q

What can MI do to the heart?

A

Leads to cardiomyopathy like DCM

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6
Q

What leads to the further loss of cells in MI?

A

The thickening and fibrosis
So drugs that prevent fibrosis will save myocytes from apoptosis
ACE inhibitors will prevent fibrosis (because angiotensin II promote fibrosis)

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7
Q

What is the preferred fuel source for the heart?

A

Fatty acids
Up to 90% of oxidative energy is derived from fatty acids
Fatty acids are broken down to acetyl CoA for energy use

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8
Q

What binds fatty acids in blood?

A

Bound to albumin, transported as triglycerides bound to apoliporprotein in VLDL or contained in chylomicron

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9
Q

What is the role of lipoprotein lipase?

A

Releases fatty acids and glycerol from triglycerides
Secreted by capillary endothelium and myocytes
Allows fatty acids to diffuse into the myoplasm

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10
Q

What is the function of CPT1?

A

The enzyme that delivers the fatty acid into the mitochondria
The key regulatory point of fatty acid oxidation
So this is a target of drugs
Decrease fatty acid oxidation = improve symptoms by decreasing cytoplasmic H+ content

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11
Q

What is the function of Carnitine acyl translocase?

A

Brings acyl carnitine (what the fatty acid becomes once it passes outer mitochondrial membrane) into the inner mitochondrial membrane
Once inside inner mitochondrial membrane, fatty acyl CoA will get degraded into acetyl CoA

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12
Q

What is the relation between malonyl –CoA and CPT1?

A

Malonyl CoA is a powerful inhibitor of CPT1

MalonylCoA is formed by the reaction catalyzed by acetyl-CoA carboxylase (ACC)

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13
Q

What is the significance of acetyl-CoA carboxylase (ACC)?

A

More ACC activity = more malonyl CoA = more inhibition of CPT1 = decrease in fatty oxidation

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14
Q

What is the significance of AMP?

A

The most important sensor of metabolism of the heart

Signals heart to increase ATP production by inhibiting ACC activity and increasing fatty oxidation

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15
Q

What does myokinase do?

A

An enzyme in the heart that takes 2 ADPs and forms ATP and AMP
That’s why AMP can inactivate acetylCoA carboxylase and increase malonyl CoA (thereby inhibiting CPT1)

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16
Q

What is the predominant receptor for glucose during fetal development?

A

GLUT 1

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17
Q

What is the predominant receptor for glucose after birth?

A

GLUT 4

Upregulated by insulin

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18
Q

What is the primary control point for glycolytic flux?

A

At the level of phosphofructokinase (PFK) under non-ischemic conditions

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19
Q

What is the significance of GAPDH?

A

GAPDH = glyceraldehyde-3-phosphate dehydrogenase
Most important regulatory point during ischemia
GAPDH activity can indicate what the heart has just gone through because it produces NADH
NADH is sensitive to cellular redox state
As NADH goes up, glycolysis slows down to allow for more fatty acid oxidation

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20
Q

What is the relationship between lactate and heart uptake in healthy exercise?

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A

If the heart is healthy, the heart takes up lactate, turns it into pyruvate and drives oxphosph
Lactate comes from skeletal muscle breakdown

21
Q

What are the key regulators of cardiac metabolism?

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A
  1. Glucose utilization is inhibited by fatty acid and/or ketone oxidation
  2. Fatty acid oxidation is inhibited by glucose catabolism
  3. glucose utilization is stimulated by inhibition of oxidative phosphorylation
22
Q

What are the key HORMONAL regulators of cardiac metabolism?

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A
  1. insulin increases carbohydrate metabolism by stimulating GLUT-4 translocation and glucose uptake and utilization
  2. Insulin lowers plasma fatty acid levels, and increases ACC activity, which in turn decreases fatty acid oxidation by increasing malonyl CoA levels
  3. Epi and NE increase myocardial conractility/energy demand/increase glycolysis + fatty acid oxidation
23
Q

Why do the mitochondria not have to be located so near to the capillaries?

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A

Because myoglobin is present that will allow adequate transport of oxygen

24
Q

What is myoglobin? Significance?

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A

An oxygen carrying molecule that is found WITHIN all muscle tissue
This allows muscle tissue to distribute oxygen to itself on its own terms
Allows muscle to survive when you hold your breath
Myoglobin helps oxygen get to the mitochondria far from the capillaries in the heart

25
What is the phosphocreatine shuttle?
A facilitated diffusion system Allows for ATP and ADP levels to stay the same Equation = PCr + ADP + H+  ATP + Cr Creatine and PCr are the ones that fluctuate in concentration while ATP and ADP levels stay the same That’s why this system is known as an ATP level buffer!
26
What is the significance of creatine kinase?
Catalyzes the reaction of the phosphocreatine shuttle Allows heart to maintain a high ATP/ADP ratio even if the energy demand transiently exceeds rate of ATP synthesis This high ATP:ADP allows for maximal calcium pumping and power output from contractile apparatus
27
What can you use to gauge oxygen consumption of heart?
PCr and creatine ratio because this is the buffer that is used to maintain ATP levels
28
What is SERCA?
Sarcoplamic reticulum Ca ATPase | Transfers Ca from cytosol to lumen of SR
29
What is the role of phospholamban?
When bound to SERCA (dephosphorylated), phospholamaban inhibits SERCA activity and promotes Ca retention in cytosol When phosphorylated, phospholamban detaches from SERCA, thereby increases calcium uptake in SR
30
What happens to ryanodine receptor in heart failure?
May leak calcium This overloads mitochondria -triggers free radicals and apoptotic cascade So overload of calcium can lead to apoptosis!
31
What is phospholemman?
A sarcolemmal protein that regulates contractility and Ca homeostasis
32
What is stunning?
A cellular consequence of transient ischemia Symptoms include i. diminished oxphosph ii. ATP partially buffered with phosphocreatine iii. Acidosis iv. Increased cytoplasmic calcium levels and buffering by mitochondria v. Restoration of oxygen renews oxidative phosphorylation, but leads to generation of oxygen free radicals vi. proteolysis of a number of cardiac proteins due to free radicals Contractile ability of the heart is DIMINISHED (protective because heart is not using as much ATP to recover from ischemia)
33
What are the key characteristics of infarction?
Prolonged ischemia (as opposed to transient ischemia in stunning) characterized by i. severe depletion of ATP and Phosphocreatine ii. intracellular acidosis iii. permanently impaired contractility iv. disrupted calcium homeostasis v. reoxygenation results in oxygen free radical generation vi. cell death This is different from an area that has been stunned or hibernated because the ischemic regions are FOREVER FUCKED That’s the significance of this lol
34
What types of cellular consequences of ischemia can the heart come back from?
Stunning | Hibernation
35
What are the key characteristics of hibernation?
Chronic, sub-lethal ischemia Describes regions of the heart with greatly decreased contractility, arising from a period of acute ischemia followed by continuing subacute ischemia Myocytes survive with decreased function Shifts expression to lower energy consuming isoforms, increased expression of enzymes needed for anaerobic glycolysis, activates ATP sensitive K cahnnels
36
How do you get cell death as a result of ischemia?
Rise in free radicals due to i. loss of glutathione peroxidase activity ii. acidic pH in tissue from hypoxic state contributes to increased free radical production in oxphosph Free radicals then damage proteins and DNA leading to activation of the death receptor pathway Caspase activation and apoptosis Also, fibrosis leads to stretch of the muscle fibers which leads to erroneous apoptotic signals as well
37
During cardiac hypertrophy, what energy source is utilized?
Increased glucose and lactate oxidation | Decreased fatty acid oxidation
38
What happens to the metabolic requirements of the heart during heart failure?
Heart switches over to net lactate production Intracellular pH decreases (increase in H+) which leads to decrease in calcium sensitivity Because of decreased calcium sensitivity, myocyte tries to compensate by increasing Ca retention in cytoplasm by decreasing SERCA activity (and increasing phospholamban activity) More calcium uptake by mitochondria = more ROS generation More ROS generation = apoptosis
39
What does an increased intracellular H+ level do?
Decreases calcium sensitivity of cardiac tissue because of downregulation of L-type calcium channels
40
What is the significance of the MMP and TIMP ratio?
The more MMPs and the less TIMP (which serves to inhibit MMP), the more collagen is produced extracellularly More MMP activity = more pathologic myocardium ECM remodeling
41
What is TIMP?
Tissue inhibitor of matrix metalloproteinases
42
What are the targets for therapeutic interventions for ischemia?
1. metabolic therapy 2. calcium handling 3. blocking free radical production or blocking apoptosis 4. increasing NO (nitric oxide)
43
What are the characteristics of metabolic therapy for cardiac ischemia?
Decrease fatty acid oxidation while increasing glucose oxidation -glucose + insulin -inhibitors of fatty acid beta oxidation (ranolazine, trimetazidine) Rationale: fatty acid utilization = more H+ in myocyte So blockage of fatty acid utilization = less H+ and acidity
44
What are the characteristics of calcium handling for cardiac ischemia?
Increase calcium pumping into SR by increasing SERCA or inhibiting phospholamban (phosphorylating it) Correcting RyR leak (Rycals) Ischemia therapeutic interventions Rationale: decrease mitochondrial activity (by using Ca) and therefore decrease ROS formation
45
What are the characteristics of blocking the free radical production or block apoptosis as therapy for cardia ischemia?
SOD and catalase mimetics Blocking mitochondrial transition pore opening Shows promise in stunning but ineffective at blocking infarction associated with ischemia-reperfusion Overexpression of Bcl-2 blocks apoptosis
46
How do you increase NO (as mechanism for ischemia therapy)?
``` Inhibiting PDE5 (increasing cGMP) Increasing NOS (nitric oxide synthase) or arginine ```
47
What is SOD?
Super oxide dismutases Enzymes that catalyze dismutation of a free radical into a non-free radical An important antioxidant
48
What is catalase?
Direct inhibitors of fatty acid metabolism | Slows progression of cell death by decreasing acidity or H+ content in myocyte
49
Why is blocking apoptosis useful to block cardiomyopathy?
Because the cells that are being apoptosed are normal and are only being signaled for death because it is being stretched by neighboring fibrosi

Cardio Week 2 (11 decks)

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