Lecture 17 - Regulation Of Cardiac Senescence In Health And Disease Flashcards
How many people in the uk are living with heart and circulatory diseases?
7.4million
What is the total annual health cost of heart and circulatory disease in the UK?
9 billion
What age is more likely to survive a heart attack - 50 or 85?
Someone who is 50
What is age related heart failure?
Decline in cardiac function
What is at risk when a “healthy patient” has a heart attack?
Increased motility and increase in severity
What are age-dependent changes that occur to cardiovascular tissues?
Diastolic dysfunction and systolic dysfunction and age remodelling
What is some examples of age remodelling?
Fibrosis, hypertrophy, decreased cardiomyocytes, inflammation, ischaemic areas and impaired regeneration
What is accumulated cellular senescence associated with?
Age related tissue dysfunction
What happens when senescence cells are moved from a mouse?
They mouse is healthier and you get
What type of expression is only seen in senescence cells?
P16
What is senescence cells driven by?
Cellular stress or replicated stress like telomeres
What can cause cellular stress?
DNA damage
What do cytokindependent inhibitors do?
Make the cell exit the cell cycle
What does SASP stand for?
Senescence associated secretory phenotype
What is antagonistic pleiotrophy?
A process that is beneficial earlier in life, it becomes detrimental in order life when there is no selective pressure
What are examples of chronic senescence?
Replicative failure/stem cell dysfunction, tissue remodelling, inflammation and senescence propagation
What can senescence occur as a result as?
Persistent DDR - (DNA damage response)
What are senescence cells casual to?
Age related pathophysiologies in multiple tissues and organs
What are the pathophysiologies due to?
Cell cycle exit - effecting tissue homeostasis and regeneration and SASP - propagating the senescent phenotype and inducing tissue remodelling and inflammation
What does cardiomyocyte senescence accumulate with?
Age
What happens when you induce senescence experimentally?
You get a young mouse with an old heart
What happens if you over express genes in cardiomyocytes that delay senescence?
You delay the heart ageing process
Switch on senescence?
High heart ageing
Switch off senescence?
Low heart ageing
What do mouse models that demonstrate myocardial remodelling cause?
Myocardial remodelling characteristic of ageing
What do the teleports protect during continuous cell proliferation?
Teleports protect the chromosome
Where are telomeres found?
At the end of chromosomes
What happens when a cell divides?
It replicates it DNA, every time you replicate the DNA you lose a bit from the end
What happens to telomeres every time DNA is replicated?
Telomeres shorten
What happens during stem cell dysfunction?
Exhaustion of the stem cell pool, reduced potential maintain tissue homeostasis
What does both telomere shortening and stem cell dysfunction lead to?
Tissue degeneration
What happens during a heart attack (as a post mitotic organ)?
Remodelling not regeneration, cardiomyocytes loss
What is TAF?
Telomere associate DNA damage
What are the stresses involved with TAF?
Oxidative stress
What does TAF contribute to?
Senescent phenotype
Does AF occur independently or dependently?
Independently of cell proliferation
What is a persistent form of DNA damage?
TAF
What are the favoured targets of persistent DNA damage?
Telomeres, if the damage occurs in the T region, the DNA damage response wont get in so wont be able to repair
Does TAF accumulate during cardiomyocytes ageing?
There is an increase in TAFs in older individuals
Could TAF contribute to senescence in a rarely cycling cardiomyocyte?
When you induce damage to the telomeres you get scenscence, TAF can occur independently of proliferation but itself can drive the senescence in the cardiomyocyte
What effect does exit from the cell cycle have on the post mitotic heart?
It has little effect on the post mitotic heart
What do senescent CMs produce?
A senescence associated secretory phenotype (SASP)
What do aged cardiomyocyte express?
A non typical senescence associated secretory phenotype (SASP)
What do secreted proteins up regulate in?
Aged cardiomyocytes
What do secreted factors from cultured aged cardiomyocytes express?
They inhibit proliferation and promote expression of marks of myofibroblast differentiation/fibrosis
What can senescence cardiac cells induce?
Senescence in other cells “bystander effect”
What does TAFs lead to?
Expression of SASP which leads to fibrosis and inflammation
What are senescent cells primed for?
Apoptosis
What do inhibitors of senescence do?
Try to stop the apoptosis process
What is hypertrophy reduced in?
Aged ink-ATTAC mice
What is an example of a drug that clears senescence cells?
Navitoclax - reduces SASP and clears senescence cells
What does navitoclax target?
Bcl2 to induce apoptosis
What does navitoclax do?
It cleats senescent cells and attenuates myocardial remodelling in vivo.
What are the benefits for navitoclax?
Fewer senescence cells, reduced fibrosis and hypertrophy
What did pre-treatment with Navitoclax and then give subject a heart attack show?
Improved survival and recovery post heart attack
