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PHYSL 404 - Cardiovascular Physiology > 18 - ECM Remodelling and Pathology > Flashcards

18 - ECM Remodelling and Pathology Flashcards

1
Q

_______ are the contractile units of the heart

A

myocytes are the contractile units of the heart

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2
Q

Defect in myocyte contractility will lead to:

A

Heart dysfunction

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3
Q

What are the three components of the extracellular matrix?

A
  1. Fibrillar collagen network
  2. Basement membrane
  3. Proteoglycans
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4
Q

Label the collagen network arrangements in the myocardium

A
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5
Q

________ network surrounds a group of muscle fibres

A

Epimysium

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6
Q

________ connect epimysial and endomysial networks

A

Perimysium

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7
Q

________ surrounds individual muscle fibers

A

Endomysium surrounds individual muscle fibers

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8
Q

Label the collagen fibres

A

(a) Collagen fibres
(b) collagen fibrils

© Collagen Molecules (triple helices)

(d) alpha chains

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9
Q

Collagen is a ________ comprised of a ______

A

Collagen is a fibrous protein comprised of a triple helix (tropocollagen)

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10
Q

How is collagen assembled? (4 steps)

A
  1. Three collagen alpha chains (Pre-procollagen) are first assembled to form procollagen (within the endoplasmic reticulum)
  2. Procollagen is secreted from the cell, the pro peptides are cleaved by procollagen peptidases, forming a collagen molecule (or tropocollagen)
  3. Multiple collagen molecules form collagen fibrils (covalent cross-linking by lysyl oxidase)
  4. Assembly of collagen fibrils form larger collagen fibres
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11
Q

Ehlers-Danlos syndrome arises from a deficiency in ________

A

Ehlers-Danlos syndrome arises from a deficiency in procollagen peptidase

  • enzyme that cleaves the ‘pro’ peptides to form a collagen molecule (tropocollagen)
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12
Q

Label the image

A
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13
Q

What are the cardiovascular complications associated with Ehlers Danlos syndrome?

A
  • Systolic murmur (valve defect)
  • Large vessel abnormalities: dilation of aortic root and pulmonary artery
  • Congenital cardiac defects:
    • Bicuspid aortic valve
    • Pulmonary valvular stenosis
    • Ventricular septal defect
    • Atrial septal defect

Recall: EDS = deficiency of procollagen peptidase

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14
Q

3 major components of the basement membrane:

A
  • collagen IV
  • Laminin
  • Fibronectin
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15
Q

Functions of the basement membrane

A
  • Provides an interface for myocyte adhesion and continuity with the extracellular matrix
  • Provides an initial barrier that will influence the exchange of macromolecules between the extracellular space and the myocyte
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16
Q

The basement membrane is divided into:

A
  • Basal lamina
    • lamina lucida
    • lamina densa
  • Lamina reticularis
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17
Q

The basal lamina (of the basement membrane) is comprised of:

A

The basal lamina (of the basement membrane) is comprised of:

  • Lamina lucida (lucid layer) - laminin, entactin, integrins
  • Lamina densa (dense layer) - Col IV (anchoring fibres)
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18
Q

Lamina reticularis (of the basement membrane) is comprised of _______

A

Lamina reticularis (of the basement membrane) is comprised of collagen III and fibronection

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19
Q

Laminin is a _______ protein (_____ chain)

A

Laminin is a heterotrimeric protein (alpha, beta, gamma chain)

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20
Q

Laminin is responsible for:

A

Bridging the cardiomyocyte to the ECM via binding to the cell surface receptors, integrin, and collagen type IV (basement membrane)

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21
Q

Fibronectin is a component of the ________ of the basement membrane

  • adhesive ________ comprised of _________
A

Fibronectin is a component of the lamina reticularis of the basement membrane

  • adhesive glycoprotein comprised of 2 almost identical polypeptide chains held together by a disulfide bond
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22
Q

function of fibronectin?

A

Connects the cell (via integrins) to the ECM (collagen)

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23
Q

What are integrins?

A

Integrins are dimeric receptor proteins consisting of an alpha and beta subunit

Serve as cell surface receptors to connect the cells (eg cardiomyocytes) to the ECM (via binding of laminin, fibronectin etc)

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24
Q

What is the function of integrins?

A

Integrins serve as cell surface receptors to connect the cells (eg cardiomyocytes) to the ECM (via binding of laminin, fibronectin etc)

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25
Q

What determines the ligand specificity of integrin?

A

The specific alpha and beta subunits in the integrin determine the ligand specificity (eg Alpha5beta1 binds to fibronectin)

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26
Q

What sort of cell signalling are integrins important for?

A

Both outside in (focus of this course) and inside out signalling

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27
Q

Paxillin and Rac lead to:

A

Cytoskeleton organization

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28
Q

Akt is important for:

A

survival

29
Q

ERK½ is important for:

A

Hypertrophy

30
Q

What is the structure of proteoglycans?

A
  • very large molecules
  • Consist of a protein core and glycosaminoglycan (GAG - long unbranched polysaccharides)
  • Form large complexes, both to other proteoglycans and to fibrous matrix proteins (collagens)
31
Q

Four functions of proteoglycans?

A
  1. Because of negatively charged GAGs, attract small cations and water, forming a porous, hydrated gel
  2. Can affect the activity and stability of proteins and signaling molecules within the matrix
  3. Serve as the “filler” substance between cells in an organism
  4. Resistant to compression, return to original shape. Hence very important in areas of compression eg Joints
32
Q

ECM accumulation =

A

fibrosis

33
Q

how is the ECM remodelled after pressure overload?

A

Pressure overloaded hypertrophy (POH) → Aortic stenosis

  • Thickening of collagen fibres
  • Increased ECM content between the myocytes
34
Q

How does volume overload hypertrophy (VOH) affect ECM remodelling?

A
  • Loss of normal ECM architecture between the myocytes
  • Poorly organized ECM
35
Q

How is ecm remodeling affected by dilated cardiomyopathy (DCM)

A
  • Dense but poorly organized ECM
36
Q

Four functions of the ECM in the myocardium?

A
  • Alignment of myocytes during systole and diastole
  • Translating single myocyte contractility into whole heart pumping function
  • A reservoir for a number of matrix-bound growth factors and cytokines
  • Essential for maintaining alignment of myofibrils within the myocyte through a collagen-basement membrane-integrin-cytoskeletal-myofibril relation
37
Q

Which two molecules are critical for regulating and maintaining the ECM integrity?

A

MMPs and TIMPs

MMPs = Matrix Metalloproteinases

TIMPs = Tissue inhibitor of metalloproteinases

38
Q

Transcription of MMP:

A

Induced by bioactive molecules, cytokines, growth factors, oxidative stress and mechanical stimuli

39
Q

What activates MMP?

A

Proteolytic activation, or by ROS (reactive oxygen species)

40
Q

Inhibition of MMP:

A

Inhibited by physiological (tissue inhibitor of metalloproteinases, TIMPs) or pharmacological inhibitors

TIMPs bind to catalytic domain of MMPs to inhibit them with a stoich of 1:1

41
Q

Where do TIMPs bind in order to inhibit MMPs?

A

N-terminus of TIMPs bind to the catalytic domain of MMPs to inhibit them

42
Q

What is the general structure of TIMP molecule?

A

Disulfide bonds at 12 strictly conserved Cystein residues maintain the six loop structure

43
Q

Label the table

Family of Tissue Inhibitor of Metalloproteinases (TIMPs)

A
44
Q

label the arterial network

A

A. Facial artery

B. Subclavian a. and v.

C. Portal V

D. Aorta

E. Descending Aorta

F. Internal Iliac a.

G. Saphenous v

H. Popiteal a

I. Common carotid a

J. Brachial a

K. Superior mesenteric a

L. Ulnar a

M. Radial a

N. External iliac a

O. Femoral a

P. Profunda femoris a

45
Q

The aorta plays important roles in:

A
  • LV performance
  • Myocardial perfusion
  • Central hemodynamics
  • Arterial function
46
Q

Label the vascular wall structure

A

A. Internal basement membrane

B. Intima

C. Adventitia

D. Media

E. External basement membrane

47
Q

The intima includes (2)

A

Endothelial cells and the internal basement membrane

48
Q

The media contains (3)

A
  • Smooth muscle cells
  • Elastin
  • Collagen
49
Q

The adventitia contains (3)

A
  • Fibroblasts
  • Connective tissue containing elastic fibres
  • The external basement membrane
50
Q

Label the vessel

A

a. endothelium
b. internal elastic intima
c. fibrocollagenous tissue
d. Tunica intima
e. smooth muscle
f. tunica media
g. fibrocollagenous tissue with external elastic lamina
h. fibrocollagenous tissue
i. Tinica adventitia

51
Q

Difference between arteries and veins

A

Arteries:

Thicker media

Collagen-rich ECM in adventitia (prevents vascular rupture at extremely high pressure)

High elastin content

52
Q

What defines the mechanical properties of the vessel?

A

The Vascular ECM

53
Q

Vascular ECM defines the mechanical properties of the vessel:

In a major artery (such as aorta) these properties include:

A
  • A highly resilient wall
  • Low energy loss during an inflation-deflation (expansion-recoil)
  • Nonlinear elasticity
54
Q

Three major structural proteins in vascular ECM

A
  1. Elastin
    • Elastic fibres (elastin + microfibrils)
      • fibrillins
  2. Collagens
    • Type I and Type III - fibrillar - impart strength on vessel wall
    • Type IV - non fibrillar - associated wtih fibrillin-1
      • connect elastic fibres to the basement membrane
  3. Proteoglycans
    • Large proteoglycans (eg versican, aggrecan)
      • Form an extensive, interconnected polymeric network in the extracellular space
    • Small proteoglycans - eg decorin, biglycan, fibromodulin, osteoglycin and lumican
      • secreted and bind to ECM molecules such as collagen, elastin, fibronectin
55
Q

Major structural proteins in the vascular ECM:

  1. Elastin
    • Elastic fibres (elastin + microfibrils)
      • fibrillins
  2. Collagens
    • Type I and Type III - _____ - impart ________
    • Type IV - ______ - associated with ______
      • connect ______ to the _______
  3. Proteoglycans
    • Large proteoglycans (eg ______, _______)
      • Form an ________
    • Small proteoglycans - eg ______, _____, ______, ______ and _____
      • secreted and bind to _________
A
  1. Elastin
    • Elastic fibres (elastin + microfibrils)
      • fibrillins
  2. Collagens
    • Type I and Type III - fibrillar - impart strength on vessel wall
    • Type IV - non fibrillar - associated wtih fibrillin-1
      • connect elastic fibres to the basement membrane
  3. Proteoglycans
    • Large proteoglycans (eg versican, aggrecan)
      • Form an extensive, interconnected polymeric network in the extracellular space
    • Small proteoglycans - eg decorin, biglycan, fibromodulin, osteoglycin and lumican
      • secreted and bind to ECM molecules such as collagen, elastin, fibronectin
56
Q

What is an elastic fibre?

A
  • An extracellular fibrous protein, predominant in the vascular ECM
  • Gives the vessel their ‘elastic property’
  • unlike collagen (dense fibres), elastic fibres are made up of relax strands
57
Q

What give vessels their elastic property?

A

elastic fibres

58
Q

Elastic fibres are made up of _____ strands

A

relax strands

59
Q

Elastin is formed on a scaffold of _______

A

Elastin is formed on a scaffold of microfibrils

60
Q

The largest component of the elastic fibre is _____

A

The largest component of the elastic fibre is elastin

61
Q

Precursor protein of elastin is:

A

tropoelastin

62
Q

Elastin is assembled along a scaffold of parallel _______

A

Elastin is assembled along a scaffold of parallel microfibrils

63
Q

What are tropoelastins?

A
  • soluble monomers which are secreted and deposited into the microfibril bundles, and cross-linked by lysyl oxidase to form insoluble elastin core
64
Q

Microfibrils are composed of numerous ___________ such as:

A

Microfibrils are composed of numerous heterogeneous glycoproteins, such as fibrillin-1 , fibrillin-2 and microfibril-associated glycoproteins (MAGP1, MAGP2)

65
Q

Fibrillin is a _______ secreted by ______ that incorporates into ______ to provide ________

A

Fibrillin is a glycoprotein secreted by fibroblasts that incorporates into microfibrils to provide a scaffold for deposition of elastin

66
Q

_______ is essential for formation of elastic fiber

A

fibrillin is essential for formation of elastic fiber

67
Q

Fibrillin-1 deficiency leads to _______

A

Fibrillin-1 deficiency leads to marfan syndrome

68
Q

_______ deficiency leads to marfan syndrome

A

Fibrillin-1 deficiency leads to marfan syndrome

69
Q

What are the life-threatening complications of Marfan Syndrome?

A

Marfan syndrome: deficiency in Fibrillin-1

  • Vascular fragility
  • aneurysms
  • The most common cause of death = aortic rupture

PHYSL 404 - Cardiovascular Physiology (17 decks)

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