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Pumps, Pipes and Electrics > The Cardiac Fibroblast and Cardiac Remodelling > Flashcards

The Cardiac Fibroblast and Cardiac Remodelling Flashcards

1
Q

What cells make up the heart?

A
  • MYOCYTES: 30-40% of cardiac cells yet occupy 2/3 of cellular volume
  • NON-MYOCYTES: 60-70%
  • Fibroblasts (most prevalent cell type)
  • Endothelial cells
  • Smooth muscle cells
  • Pericytes
  • Neuronal cells
  • Inflammatory cells
  • Progenitor cells
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2
Q

How to myocytes and fibroblasts interact in the heart?

A

Both myocytes and fibroblasts are found in close proximity to one another in the heart
-There is evidence that gap junctions form between the two cell types to allow them to communicate and quickly propagate action potentials (maintains the syncytium)
THIS EVIDENCE has been seen using Rabbit Heart Models and stains for Myocytes, Fibroblasts and Gap Junctions (KOHL, HEART RHYTHM, 2012)

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3
Q

How do gap junctions allow communication?

A

They allow action potential propagation through the movement of ions, but they allow communication between cells via the movement of second messengers

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4
Q

How does fibrosis prevent action potential propagation?

A

Excess fibrosis and the laying down of collage disrupts the gap junctions and prevents ions and second messengers from flowing freely between cells.
-Electrical coupling is therefore disturbed and arrhythmias can occur

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5
Q

How are fibroblasts regulated?

A

They are able to respond to blood cytokines and growth factors that are delivered through capillaries
-They are also able to synthesise and secrete their own bioactive molecules that act in an autocrine or paracrine manner

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6
Q

How are fibroblasts associated with the extra cellular matrix?

A

Fibroblasts are physically associated with the collagen-based ECM through receptors such as DDR2 and Integrins

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7
Q

What is the healing process after MI?

A
  1. Cell death due to ischaemia
  2. Acute inflammatory response
    - innate immune response is triggered and neutrophils and macrophages are recruited
    - cytokine and chemokine release attracts more cells
  3. Formation of GRANULATION TISSUE
    - there is phenotypic differentiation of fibroblasts to myofibroblasts
    - Both myofibroblasts and macrophages accumulate in the damaged tissue
    - Macrophages release MMPs which degrades the ECM
    - Neovascularisation to restore blood flow
  4. MATURATION PHASE
    - Myofibroblasts deposit collagen types I and III
    - Myofibroblasts then contract to reduce the area of scar tissue
  5. RESOLUTION OF INFLAMMATORY RESPONSE
    - Action of anti-inflammatory cytokines e.g IL-10 and TGF-b
    - Majority of myofibroblasts now undergo apoptosis but a few remain for several years
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8
Q

What is the long term outcome of healing post MI?

A
  1. Excessive collagen deposition
  2. Fibrosis
  3. Adverse remodelling
  4. Heart failure
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9
Q

Where do cardiac fibroblasts come from?

A

From Epicardial Epithelial Cells by Epithelial Mesenchymal Transformation
-This is a very different lineage from other cardiac cells and also from other fibroblasts in the body

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10
Q

How are fibroblasts identified?

A

There are no definitive markers for identifying fibroblasts due to the hetergeneous nature of fibroblasts and their similarity to other cell types

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11
Q

What are the most commonly used antibody stains for fibroblasts?

A
  1. Vimentin (a filamentous cytoskeletal protein)
  2. DDR2 (collagen receptor)
  3. FSP (fibroblast specific protein)
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12
Q

How can Myofibroblasts be identified?

A

Myofibroblasts are differentiated forms of fibroblasts and contain contractile units called alpha-Smooth Muscle Actin
-These a-SMCs can be identified using stains and can differentiate them from cardiac myocytes because they do not stain for Smooth-Muscle Myosin Heavy Chain (SM-HC)

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13
Q

What roles do cardiac fibroblasts play?

A
  1. Production of cytokines and growth factors
  2. Matrix synthesis
  3. Matrix degradation by secretion of MMPs and inhibition of TIMPs (tissue inhibitors of Metaloproteases)
  4. Myofibroblast differentiation
  5. Fibroblast migration
  6. Fibroblast proliferation
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14
Q

How do fibroblasts behave under normal physiological conditions?

A

They are QUIESCENT CELLS

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15
Q

What happens to cardiac fibroblasts during remodelling?

A

They become activated due to altered levels of growth factors, cytokines and reactive oxygen species

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16
Q

How are fibroblasts different from myocytes?

A

Fibroblasts once activated can become highly proliferative and migrate to different areas, whereas myocytes are unable to proliferate.
-Fibroblasts tend to migrate to the infarct zone where they undergo phenotypic differentiation into myofibroblasts

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17
Q

How are myofibroblasts different from fibroblasts?

A

They begin to express alpha-smooth muscle actin, focal adhesion proteins and extracellular matrix proteins
-All of these new proteins confer TENSILE properties and so the myofibroblast is able to contract and reduce the size of the infarct area
(focal adhesion proteins are needed to hold on to the ECM and contract it)

18
Q

How do fibroblasts modify the extracellular matrix?

A

They express matrixmetalloproteases which degrade the ECM, and they can also promote its preservation through expression of TIMPs-tissue inhibitors of metalloproteases

19
Q

What are some pro-inflammatory cytokines that fibroblasts produce?

A

IL-1
IL-6
IL-8
TNF

20
Q

What are some pro-fibrotic growth factors that fibroblasts produce?

A

TGF-Beta

GTGF

21
Q

What are some angiogenesis-inducing factors that fibroblasts produce?

A

PDGF

VEGF

22
Q

What makes cardiac fibroblasts essential?

A
  • They’re needed for maintenance of normal cardiac development and structure
  • They support adaptive changes in heart structure both physiologically and pathologically
  • They induce repair of the heart in scar formation and healing post-MI
  • Prevent cardiac rupture by increasing tensile wall strength
23
Q

Why are fibroblasts detrimental?

A
  • Excessive, sustained fibroblast proliferation and ECM deposition results in Fibrosis and a stiff heart and restricted contraction/relaxation
  • ECM deposition disrupts action potential conduction by interferring with Gap junctions and so arrhythmias can result
24
Q

What stimulates production of Myofibroblasts via differentiation of fibroblasts?

A
  1. Mechanical tension (infarct area and hypertrophy)
  2. TGF-B
  3. Fibronectin (FN-EDA)
  4. Collagen VI
25
Q

What do myofibroblasts show increased expression of?

A
  1. Contractile proteins e.g alpha-smooth muscle actin and Vimentin
  2. Focal Adhesion Proteins e.g Tensin and Integrins
  3. Cell surface receptors e.g Ang I
  4. ECM proteins e.g Collagen I and III
26
Q

What type of characteristics do they extra proteins produce in myofibroblasts?

A

They induce TENSILE CHARACTERISTICS i.e the myofibroblast can contract
-This contraction allows ECM contraction and reduction in the size of an infarct or damaged area

27
Q

How do we know about these tensile characteristics?

A

Nirwenhoven, Matrix Biol,2013 used collagen gel discs to demonstrate the tensile characteristics of myofibroblasts

  • Myofibroblasts were placed on the gel discs and the surface are of the collagen discs became reduced
  • Shows that upon contact with collagen i.e ECM, myofibroblasts contract
28
Q

Where do myofibroblasts come from?

A

It was originally thought that myofibroblasts came solely from differentiation of fibroblasts in the heart.
However there is increasing evidence that they also come from elsewhere
-CELL LINEAGE EXPERIMENT have now shown that myofibroblasts can be derived from epi- and endothelial cells in a process termed ENDO-/EPITHELIAL TO MESENCHYMAL TRANSFORMATION (as is the case for fibroblasts)
-Studies have also shown that myofibroblasts can be derived from progenitor stem cells in the heart or blood (bone marrow dervied fibroblasts are known as Fibrocytes)
-AND resident smooth muscle cells may de-differentiate into cardiac myofibroblasts

29
Q

Where do the majority of cardiac myofibroblasts come from?

A

The relative contributions of different sources of myofibroblast vary greatly in different settings i.e physiological and pathological
BUT
it still appears that the majority of cardiac myofibroblasts come from the differentiation of resident cardiac fibroblasts

30
Q

In pro-fibrotic environments, what proteins are produced to allow ECM synthesis?

A
  • Collagens I and III
  • Laminins (structural ECM protein)
  • Fibronectins (structural ECM protein)
  • GAGs (glycosaminoglycans)
  • TIMPS (inhibits breakdown of ECM)
31
Q

In anti-fibrotic environments, what proteins are produced to inhibit ECM synthesis?

A
  • MMPs

- ADAMS and ADAMTS (proteases that breakdown elements of the ECM)

32
Q

What are matrixmetalloproteases?

A
  • A family of >25 zinc-dependent endopeptidases
  • Can degrade components of the ECM
  • MMPs are mostly secreted from fibroblasts but can also come from cell membranes called Membrane-Type MMPs
  • Expression of MMPs is usually low (don’t want myocyte slippage in healthy phenotype) but expression can be massively upregulated when needed in response to pro-fibrotic cytokines such as TGF-B
  • MMPs are secreted as inactive zymogens and require enzymatic activation
  • MMPs are inhibited by TIMPs 1-4
  • Cardiac fibroblasts express MMPs 1-14
33
Q

What stimulates MMP production?

A

TGF-B and IL-1

34
Q

What inactivates MMPs?

A

TIMPs and Ang II

35
Q

What is IL-1?

A

-An inflammatory cytokine that shows elevated levels following MI
-Cardiac fibroblasts are particularly sensitive to the effects of IL-1
IL-1 causes fibroblasts to:
-Produce more pro-inflammatory molecules
-Increases angiogenesis through production of VEGF
-Increase cell migration (to move fibroblasts to where they are needed)
-Increase ECM degradation (MMP production-to allow for remodelling)
-Decrease ECM synthesis (until ready to produce more)
-Decrease myofibroblast production (IL-1 is released in the early stages of injury and we don’t want infarct contraction until some remodelling has taken place)

36
Q

How might cardiac fibroblasts be used therapeutically?

A

There is potential that cardiac fibroblasts could be used as a therapeutic target to protect/enhance cardiac repair but inhibit adverse remodelling

37
Q

How might cardiac fibroblasts be targeted?

A

There are no direct fibroblast therapies yet but direct reprogramming, genetic therapies and microRNAs all hold potential

38
Q

What drugs already have an effect on fibroblasts?

A 
it is thought that:
1. ACEis and ARBs
2. Beta Blockers
3. Statins
^all play a role in modulating fibroblasts
39
Q

How do ACEis and ARBs affect fibroblasts?

A
  • As well as lowering blood pressure, ACEis and ARBs may reduce adverse myocardial remodelling and reduce heart failure mortality
  • Angiotensin II is known to have profibrotic effects on the heart
  • Ang II stimulates:
  • cardiac fibroblast stimulation
  • myofibroblast differentiation
  • ECM synthesis
  • Inhibits MMPs

SO, by inhibiting Ang II we are inhibiting all of these effects thus reducing fibrosis and reducing adverse remodelling

40
Q

How do beta blockers affect cardiac fibroblasts?

A

(Turner, Cardiovascular Res, 2003)

  • Block the effects of adrenergic receptors so reduce blood pressure and heart rate
  • But have also been shown to reduce fibroblast proliferation so reducing fibrosis
41
Q

How do statins affect fibroblasts?

A

(Porter, 2011)
-Statins inhibit the enzyme HMG CoA Reductase needed to synthesise cholesterol
-Improves vascular function by raising levels of HDLs whilst lowering LDLs
Statins have also been shown to reduce adverse remodelling so appear to have CHOLESTEROL INDEPENDENT PLEIOTROPIC EFFECTS
-Lipid intermediates in the cholesterol pathway are needed to synthesise G-proteins Ras and Rho
-Statins inhibit this so Ras and Rho signalling cannot occur-it is thought that this cellular signalling is involved in the effects of statins upon remodelling
-Simvastatin shown to reduce TNF induced proliferation of fibroblasts and also reduces MMP-9 needed for ECM degradation

42
Q

Summary of Fibroblasts:

A
  1. Essential for normal development and physiological functions of the heart
  2. Play a key role in physio- and pathological remodelling
  3. Fibroblasts are potential therapeutic targets to aid repair or reduce adverse myocardial remodelling

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