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Pumps Pipes and Electrics > Lecture 9 - The cardiac fibroblast > Flashcards

Lecture 9 - The cardiac fibroblast Flashcards

1
Q

What cells is the heart made from?

A 
1/3 cardiomyocytes
2/3 non-myocytes
- majority fibroblasts 
-endothelial cells
-SMC
-pericytes
-neuronal cells
-inflammatory cells
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2
Q

What happens to the Constitution of cells after an MI

A

neutrophils / monocytes infiltrate the area

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3
Q

what happens to the constitution of cells after cardiac fibrosis

A

-number of cardiac fibroblasts / myofibroblasts increases

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4
Q

what connects myocytes and fibroblasts together?

A

gap junctions

- allows movement of cytoplasmic contents and transmission of electrical impulses

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5
Q

Role of connexin-43 in showing the relationship between myocytes and fibroblasts

A

connexin-43 = protein in gap junctions
-found at myocyte edges where myocytes meet
fibroblasts
-staining between cells suggests their connection

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6
Q

what can proliferation of fibroblasts cause?

A

laying down of excess collagen can interfere with electrical activity and cause arrhythmia

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7
Q

How can capillaries signal fibroblasts?

A

through releasing cytokines and growth factors

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8
Q

how do fibroblasts regulate their own cellular function?

A

through release of bioactive molecules in an autocrine and paracrine manner

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9
Q

how are fibroblasts associated with the ECM

A

physically associated through specific receptors –> DDR2 and integrins

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10
Q

what are the first two stages of an MI?

A
  1. cell death –> oxygen / glucose depletion
  2. acute inflammatory response
    - inflammtory cells arrive –> chemoreceptors / cytokines
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11
Q

Explain the formation of granulation tissue post-MI

A
  1. fibroblasts converted to myofibroblast
  2. myofibroblast and macrophage accumulation
  3. ECM degradation
  4. neovascularisation
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12
Q

explain the maturation phase post-MI

A
  1. scar formation –>ECM deposition

2. scar contraction –> myofibroblasts

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13
Q

explain the last two stages of Post-MI

A
  1. resolution of inflammatory response
    - anti-inflammatory cytokines
    - myofibroblast apoptosis
  2. long term
    - fibrosis –>adverse remodelling –> HF
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14
Q

where do cardiac fibroblasts come from

A

distinct lineage from cardiomyocytes and other sources of fibroblasts
-Derived from epicardial epithelial cells by epithelial-mesenchymal
transformation

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15
Q

list fibroblast markers

A

Vimentin, DDR2, PDGFRA, (FSP/S100A4)

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16
Q

list myofibroblast markers

A

Vimentin, DDR2, PDGFRA, (FSP/S100A4)

a-SMA (but not SM-MHC)

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17
Q

what phenotype do cardiac fibroblasts have in culture

A

myofibroblast phenotype

18
Q

what happens to cardiac fibroblasts in cardiac remodelling

A
  • highly proliferative
  • migrate to different areas such as the infarct zone
  • undergo modulation to myofibroblasts
19
Q

what is the active phenotype of myofibroblasts characterised by?

A
  • increased expression of contractile proteins ( alpha smooth muscle / actin ) / focal adhesion proteins / extracellular matrix proteins
  • this allows them to physically contract around wound edges
20
Q

how do fibroblasts interact with the ECM?

A

modulators of ECM

  • through expression of ECM proteins
  • regulating production of ECM-degrading proteases such as matrix metalloproteinases (MMPs), and their natural inhibitors TIMPs
21
Q

what can cardiac fibroblasts secrete?

A

synthesise high levels of proinflammatory (e.g. IL-1, IL-6, IL-8, TNF) and profibrotic cytokines (e.g. TGF-beta, CTGF) and growth factors (e.g. PDGF and VEGF) - stimulators of angiogenesis.

22
Q

Role of CF in cardiac remodelling?

A
  • proliferation
  • matrix synthesis
  • cytokine and growth factor secretion
  • migration
  • myofibroblast differentiation
  • matrix degradation
23
Q

What are the essential roles of CF? beneficial

A
  1. maintenance of normal cardiac structure and function
  2. supporting adaptive and structural changes in heart structure
  3. repair of heart –> scar formation and healing after MI
  4. preventing cardiac rupture
24
Q

What are the detrimental roles of CF?

A
  1. Fibrosis
    - excessive and sustained proliferation and ECM deposition
  2. Arrhythmia
    - disturbance and blockage electrical conduction
25
Q

what stimuli cause the conversion of CF to myofibroblast?

A
  • mechanical tension
  • TGF-B
  • FN-EDA / collagen VI
26
Q

what are increased in expression in myofibroblasts compared to CF?

A
  1. contractile proteins –> a-SMA / vimentin
  2. focal adhesion proteins –> tensin / integrins
  3. cell surface receptors –>TBRII / AT1R
  4. ECM proteins –> collagen I / III
27
Q

what characteristics does myofibroblasts have compared to CF?

A

increased tensile characteristics

contraction of ECM

28
Q

what happens to the number of myofibroblasts after an MI? and how is this measured?

A

high number of a-SMA positve myofibroblasts

29
Q

What is the effect of TGF-B on CF?

A

increased a-SMA expression
organisation into filaments
increased ability to contract collagen gels
Nieuwenhoven FA et al

30
Q

where do myofibroblasts originate from?

A
  • significant proportion from the fibroblasts in the heart
  • endothelial / epithelial cells through EndMT / EMT
  • resident SMC
31
Q

what is pro-fibrotic in terms of ECM?

A

production of ECM leads to fibrosis

  1. ECM synthesis
    - collagens / laminins / GAGs / fibronectin
  2. Inhibition of ECM degradation
    - TIMPs ( reduce action of MMPs)
32
Q

what is anti-fibrotic in terms of ECM?

A

reduction in ECM

  1. ECM degradation
    - MMPs / ADAMS / ADAMTS
    - break down structural proteins in ECM
33
Q

What are MMPs

A
  • family > 25 Zn dependent proteases
  • degrade all elements of ECM
  • mostly secreted from cells
  • low expression but can be induced
  • secreted as inactive zymogens
  • inhibited by TIMPs
34
Q

what are signals that regulate the expression and activity of MMPs?

A

Increase activity generally by inflammatory signals –> cytokines / ROS
Decreased activity by profibrotic signals

35
Q

what do CF’s release?

A
  • growth factors and cytokines
  • produce molecules that have opposing effects
  • depend on the signals released from the surroundings
  • they release –> inflammatory / anti-inflammatory / fibrotic / anti-fibrotic / apoptoic / mitogenic / angiogenic / anti-angiogenic
36
Q

What does IL-1 do in cultured CF tissue?

A 
- similar gene expression to post-MI
Stimulates
1.pro-inflammatory cytokines/chemokines/ adhesion proteins
2.angiogenesis
3. cell migration
4.ECM degradation
Inhibits
1. ECM production
2. myofibroblast differentiation
37
Q

what is the purpose of CF targetted therapy ?

A

ensure cardiac repair but prevent adverse remodelling and fibrosis

38
Q

what are potential CF therapies?

A

-direct reprogramming
-genetic therapies
miR-21

39
Q

what cardiovascular drugs target CF?

A

ACEi
Beta blockers
statins

40
Q

how do ACEi and ARBs effect CF?

A

reduce adverse remodelling
AT-II stimulates CF proliferation
AT II increases matrix synthesis/ proliferation /myofibroblast differentiation

41
Q

How do Beta blockers effect CF?

A

reduce adverse cardiac remodelling
-beta agonists increase the proliferation of CF in cultures
-beta blockers reduced CF proliferation
Turner NA & Porter KE

42
Q

how do statins effect CF?

A 
reduce adverse cardiac remodelling
inhibit HMG-CoA reductase 
reduce proliferation of cardiac fibroblasts
reduce MMP secretion
prevent cardiacmyocyte hypertrophy

Pumps Pipes and Electrics (12 decks)

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