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BSc module 3 > Extra-cellular matrix, fibroblasts and fibrosis > Flashcards

Extra-cellular matrix, fibroblasts and fibrosis Flashcards

1
Q

3 classes of molecules in ECM

A
  1. Structural proteins (collagens and elastins)
  2. Adhesive glycoproteins to attach cells to matrix
    (fibronectins and laminins)
  3. Proteoglycans (protein-polysaccharide complexes)
    to embed the structural proteins
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2
Q

Main structural protein in the heart

A

Collagen

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3
Q

How does collagen act?

A

Scaffold for cells during the force of contraction
Prevents myocyte slippage
Provides elasticity

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4
Q

Main types of collagen in the heart

A

Collagen type I and III

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5
Q

Composition of collagen type I

A

two alpha1- chains and one alpha

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6
Q

What is collagen produced in

A

Fibroblasts

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7
Q

Single collagen pro-peptide has>

A

N terminus and C terminus and in centre has a glycine followed by 2 different repeats (different collagens may have different - in collagen type I - two alpa1 and 1 alpha2)

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8
Q

What happens once pro peptides synthesised and where

A

Coil into a tight right handed triple helix of 3 alpha chains. In RER

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9
Q

What happens after triple helix of collagen forms

A

Excreted into extracellular space

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10
Q

What happens after excretion of collagen?

A

Converted into collagen from procollagen by the enzymatic cleavage of the N- and C-propeptides

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11
Q

What do adhesive glycoproteins consist of

A

Adhesive glycoprotein consisting of 3 chains: alpha beta and gamma

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12
Q

What do adhesive glycoproteins proteins do?

A

Bridges between structural ECM molecules to reinforce this network, as well as to connect the ECM to cells within the extracellular space

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13
Q

Main glycoprotein in the heart and what is it produced by?

A

Laminin

produced by cardiac myocytes, vascular smooth muscle cells and endothelial cells.

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14
Q

What do proteoglycans do?

A

Bind everything together more strongly - higher order structur

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15
Q

Primary function of proteoglycans. Properties for this

A

Bind water to provide hydration and compressive resistance.

biochemical and hydrodynamic characteristics due to presence of glycosaminoglycans (GAGs)

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16
Q

Structure of proteoglycan

A

Core protein (long part), covalently linked to GAGs

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17
Q

What are GAGs

A

long, negatively charged, linear chains of disaccharide repeats

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18
Q

Cell type associated with regulating ECM

A

Fibroblasts

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19
Q

Highest cell number in heart vs volume

A

Fibroblasts

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20
Q

Development of fibroblasts

A

Epicardial and endocardial layers can undergo mesenchymal transformation - produce resident fibroblats

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21
Q

Impact of injury on fibroblasts

A

BM derived cells can be recruited and transformed into cardiac fibroblasts

22
Q

Functions of fibroblasts

A
  1. Primary function is to maintain and regulate ECM
  2. Can produce a number of active peptides (e.g.
    cytokines, growth factors, peptides)
  3. Contribute to production of ECM proteins (collagens,
    elastin, fibronectin)
  4. Produce ECM-regulatory proteins, matrix
    metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs)
23
Q

What do MMPs do?

A

degrade ECM protein

24
Q

What do TIMPs do

A

inhibit MMP

25
Q

How do MMPs affect electrophysiology

A

Non-excitable, do not produce APs

BUT can couple with myocytes to transfer current

26
Q

Resting Vm of fibroblasts

A

-30mV - less negative than cardiomyocyte

27
Q

Currents in fibroblasts

A

K, Na, and other minor currents

28
Q

Do fibroblasts couple with myocytes

A

in vitro culture leading to a higher probability of spontaneous depolarisation.
Not clear whether this occurs in intact tissue

29
Q

Well exercised heart - impact on structure

A

Myocyte hypertropy
No fibrosis
Increased vasculature density.
Does increase some of ECM

30
Q

Pathology impact

A

Myocyte death
Increased fibroblast proliferation/fibrosis
Decreased vasculature density

31
Q

Impact of disease on ECM

A

Either excess ECM
or
ECM breakdown

32
Q

Consequence of increased ECM breakdown in disease

A

cardiac tissue destruction → High levels of MMP1 results in collagen loss and reduced contractility in cardiomyopathies

33
Q

Consequence of excess ECM in disease

A

pathological fibrosis following tissue injury

Leads to areas of inactivity, plus ↑cardiac stiffness, ↑rigidity

34
Q

Impact of fibrosis

A

areas of inactivity as well as ↑ cardiac stiffness

35
Q

How is scar classified?

A

Degrees of density
Interstitial – fibrosis along the fibril bundles Deposition in the direction of the collagen orientation
Diffuse - everywhere
Patchy - larger areas of red, the other unaffected areas
(Collagen in the wall of the blood vessel is normal) Compact → around an infarct area

36
Q

Consequence of scar

A

separation of strands of myocardium - this forces excitation waves to take anisotropic, circuitous paths - may low re-entry excitation

37
Q

What mediates fibroblasts modulation of cardiomyocyte electrical activity by fibroblasts

A

Voltage-gated Na+

THEORY - ONLY APPLIES IF COUPLED

38
Q

How do fibroblasts affect AP in myocytes

A

Whenever the cardiomyocyte membrane potential is different from -30mV, current flows through gap junctions between the cells to pull myocytes voltage towards -30, leading to shortened APD

39
Q

Talk through AP change if fibroblast coupled to myocyte

A

myocyte-fibroblast coupling leads to slow conduction and shorter APDs, which can result in re-entry

40
Q

What are myofibroblasts?

A

Remodelled fibroblasts become these from injury

41
Q

Properties of myofibroblasts

A

More mobile
Contractile
Protective mechanism

42
Q

What is alphaSMA

A

Smooth muscle cell markers that are not typically expressed in quiescent fibroblasts but are in myofibroblasts

43
Q

How do myofibroblasts increase contractility

A

Connect to fibronectin via specialized adhesion complexes called fibronexus

44
Q

What is another effect of increased contractile force by myofibroblasts?

A

mediates further fibroblast recruitment to site of injury

45
Q

What are MMPs a therapeutic target?

A

They control ECM remodelling

46
Q

Effect of broad spectrum MMP inhibition

A

attenuate the degree of post-MI LV dilation and expansion of the infarct in a pig model – but broad spectrum is feared to have systemic side effects

47
Q

Specific MMP inhibitor

A

PG116800 inhibits MMP-1 and MMP-7

Early clinical trials in premier study failed to reduce LV remodelling or improve clinical outcomes after MI

48
Q

Other therapeutic targets - RAS

A

Modulation of the renin-angiotensin (Ang) system using Ang converting enzyme (ACE) inhibitors or Ang receptor antagonists (e.g. losartan) appear to be effective in reducing cardiac fibrosis in a variety of models in animals and humans

49
Q

Other therapeutic targets: TGF-b

A

plays a central role in fibroblast activation inducing ECM deposition by supressing MMP and inducing TIMP expression
Wounds treated with anti-TGF-b showed reduced ECM synthesis and scarring
Inhibitors of TGF-b receptors are also considered as potential anti-fibrotic compounds

50
Q

Other therapeutic targets: Endothelin

A

Production of ECM and fibroblast differentiatio. Endothelin receptor antagonism may be considered as an appropriate therapy for fibrosis
Currently endothelin receptor blockers (bosentan) are used for the treatment of pulmonary arterial hypertensionn

51
Q

Other therapeutic targets: Platelet derived growth factor

A

(PDGF) is responsible for inflammatory and smooth muscle cell migration and proliferation to the site of injury.
PDGF receptor inhibitor Imantinib mesylate delays wound closure together with reduction in myofibroblast number and fibronectin and collagen I

52
Q

Other therapeutic targets: TNF-a

A

TNF-a is a pro-inflammatory cytokine expressed at the site of injury could also be a potential target since its overexpression in animal models develop heart failure

BSc module 3 (10 decks)

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