Matrix metalloproteinases (MMPs) are critical enzymes involved in cardiovascular disease, particularly in processes like atherosclerosis, plaque rupture, and heart failure. They play a role in the remodeling of the extracellular matrix, affecting structural integrity and cellular functions, while their activity can be influenced by various risk factors and tissue inhibitors. MMPs have potential as therapeutic targets and diagnostics, although they are not recommended as routine biomarkers due to insufficient predictive value.

1. Matrix Metalloproteinases
in Cardiovascular disease
Moderator: Prof Kim Vaiphei

2. Outline of class
 What are matrix metalloproteinases?
 Types of MMPs
 Tissue inhibitors of Metalloproteinases
 Role in atherosclerosis
 Role in plaque rupture
 Role in heart failure
 Diagnostic and Prognostic utility
 Therapeutic potential
 Summary

3. What are Matrix Metalloproteinases?
 Metal linked enzymes
 Zn – Needed for protease activity
 Ca – Stability and execution of action
 Proenzyme : Latent due to pro-peptide domain
 Hydrolysis of cysteine bond – uncovers enzymatic
site
 Potent protein degradation and modifying
enzymes
Nagase H et al. Cardiovascular Research. 2006: 562-573

5. Types
Enzyme name MMP class
Collagenases MMP-1, MMP-8, MMP-13
Gelatinases MMP-2, MMP-9
Stromelysins MMP-3, MMP-10, MMP-11
Membrane type-MMPs MMP-14, MMP-15, MMP-16,
MMP-17, MMP-24, MMP-25
MT-MMPs process signalling peptides - cytokines
Intra-cellular MMP – actin-myosin interface
Liu P et al. Advances in Vascular Biology. 2006:22

6. Production and Regulation
Cells which produce Regulators of transcription
Smooth muscle cells TNF-
Myocytes Interleukins
Fibroblasts PDGF
Endothelial cells CD40 ligands
Monocytes / Macrophages
T-cells
Chen Q et al. Mediators of Inflammation. 2013:1-14

7. Activation signals
 Oxygen free radicals
 Ischemic triggers - thrombin and chymase
 Angiotension-converting enzyme
 Plasminogen activators
 Plasmin
Gaffney J. Matrix Biology. 2015:44-46

8. Inhibitors
 Tissue inhibitors of metalloproteinases
 Physiological : TIMP – I to 4
 Artificial : Tetracycline family of antibiotics,
synthetic inhibitors
Castro M et al. Pharmacological Research.2011:511-560.

9. Liu P et al. Advances in Vascular Biology. 2006:22

10. Role of extracellular matrix
 Structural integrity of heart and blood vessels
 Framework for cell anchoring and function
 Mediates cell adhesion, cell phenotype and cell-cell
communication
 Integrates mechanical force and lines of force transmission
 Mediates diastolic stiffness
 Promotes cell survival or apoptosis
 Reservoir of growth factors and cytokines
Liu P et al. Advances in Vascular Biology. 2006:22

11. MMP in atherosclerosis
 Plaque – Lipid core + external fibrous cap + macrophages
 Fibrous cap matrix – collagen (strength) + elastin (flexibility)
 MMP role in remodelling - resorbed and re-deposited
 In stable conditions – remodelling is balanced
 MMP-9 & MMP-3 in advancing edge of plaque
 TIMPs increased in areas of calcification – Natures way of
stabilising remodelling process
Liu P et al. Advances in Vascular Biology. 2006:22

12. MMPs in plaque rupture
 Proinflammatory conditions
 Remodelling shifted in favour of resorption of matrix – weakness of
fibrous cap
 Result in plaque rupture
 MMPs increased at sites of potential weakness
Newby A. Matrix Biology. 2015:157-166

14. Risk factors – activate MMPs
 Smoking
 Diabetes
 Homocysteine Increased oxidative stress
 Increased lipids
 Smoking
 Diabetes
 Homocysteine Increased oxidative stress
 Increased lipids
Ruddy JM et al. Journal of Vascular Research.2016:1-16

15. MMPs in following infarction
 MMP activity – increase in progression of heart failure
 MMPs increased within hours of the infarction – followed by fall in
levels
 Second wave of MMP activation – ventricular dilation and heart
failure
 TNF- related to the increased production of MMP-9 & MMP-2
Pennell KY et al. Progress in Mol Biology and Translational Science. 2017:75-
100

17. MMPs as diagnostic or
prognostic markers
 MMPs are released into blood – Can be quantified
 MMP-9 – most efficient prognostic information
 But lacks conclusive predictive value
Halade GV et al. Pharmacology & Therapeutics. 2013:32-40
MaAloon CJ et al. Heart failure and cardiomyopathies.. 2017:639

18. MMPs –stem cell mobilisers
 MMP-9 in bone marrow – releases stem cells into circulation
Jane HP et al. Vascular Health and Risk Management. 2012:99-114

19. Therapeutic opportunities
 Elastase inhibition in viral myocarditis – decrease cardiomyopathy
 In setting of A-V fistula – MMP inhibitor effectively decrease cardiac
dilation and preserve ventricular function
 Problem of fibromyalgia as a side effects
 Hence, indirect inhibition of activation of MMPs- ACE inhibitors,
statins, acetylsalicylic acid, TNF inhibitors

21. Take home messages
 MMPs are a family of potent matrix digesting enzymes
 Pro form in matrix secreted by many types of cells
 Activators, regulators and inhibitors
 Role in atherosclerosis, plaque rupture and myocardial
remodelling
 Not a good biomarker for routine practice
 Role in mobilising stem cells
 Therapeutic benefits are from indirect methods of preventing
activation of MMPs

22. Doubts … Questions ….