Cardiac Cell Biology Flashcards
WHat do skeletal muscle and cardiac muscle have in common
basal lamina
striated
contractile proteins similar
mechanism of contraction is similar
What are some factors about cardiac muscles that are unique against skeletal?
involuntary
smaller
1-2central uclei
branched
more vascular
more mitochondria (2x)
more myoglobin
more lipid droplets
intercalated discs
CICR
WHich is cardiac and which is skeletal?
Left is cardiac and right is skeletal
describe a cardiac myocyte
CMs branch (arrowheads)
intercolated discs (arrows) form boundaries between CMs
cross-striations are obscure, relative to skeltal muscle
nuclei centrally located
What is seen in the green outline what is within it?
myocytes! myofibrils!
How are sarcomeres aligned in cardiac muscle? are there more or less mitochondria in cardiac compared to skeletal? Where is the nucleus?
- sarcomeres aligned as skeeltal musle
- many more mito
- lots of glycogen
- central nucleus
- endothelial cell (mkaing a capillary)
- profuse mitochondria
WHat is the blue and what is the orange? What is the yellow?
blue is basal lamina between 2 adjacent cardiomyocytes
orange is Sarcoplasmic Reticulum which surrounds each myofibril
there are 6 thin filaments per thick filament
What is the function of the intercalated discs (IDs)?
- sarcolemmal specializations that mediate CM-CM binding
- they enable CMs to work as a single unit as if they were in syncytium
How do IDs connect? (structure)
they connect in a starcase fashion
- transverse part: transmits force
- a modified Z-band (Z-line)
- consists of fascia adherens, comprised of N-cadherins, and desmososmes
- lateral part: mediates CM-CM signaling
- gap junctions (nexi) and a few desmosomes
WHat is the yellow? what is the blue ?
- yellow-last I bands attaching to the modified Z-line
- blue-gap junctions are along this lateral border
IDs cross adjacent in stepwise fashion
the fascia adherens is a zonula adhernes that doesn’t encircle the cell
what is the fascia aderens?
N-cadherins and desmosomes
WHat is this image illustrating?
N-cadherin in the intercelular space
WHat junctions make up the lateral part of the intercalated disc?
gap and desmosome junctions
1 connexon is made up of _______
1 connexon is made u of 6 connexins
How does excitation (electrical) occur?
- Action potential: depolarization of the T tubules leads to depolarization of the SR
- phase 2 AP: L-type Cav1.2 leads to Ca influx (CICR)
- subunit through which Ca ions enter
- Encoded by CACNA1C: mutated in long QT arrhythmia
- does not bind to SR
- Ca binds to Ryr leading to release of Ca from the sarcoplasmic reticulum, intracellular Ca increases and binds to troponin causing the physical phase of contraction
- The Action Potential (AP) wave caused by brief influx of Na+ into CMs initiates a wave of depolarization along the sarcolemma, which proceeds into the T-tubules. This results in opening of L-type Ca++ channel proteins in the T-tubule membrane – notably Cav1.2 – which causes slightly increased Ca++ levels inside the CM, near the SR. This induces a Ca++-induced Ca++ release from the SR – termed a “CICR” – mediated by the binding of Ca++ (not binding of Cav1.2) to ryanodine receptors (RyR) in the SR membrane. Highlights of this process that should be noted are as follows:
How does contraction occur?
- Ca binds troponin C causing tropomyosin to move
- ATP hydrolysis activates the myosin head
- The myosin head binds actin
- Power stroke: myosin pulls actin into A-band, thus sarcomere shortens leading to contraction
What are the diffeences between Cav1.1 and Cav1.2
Cav1.1 is in skeletal muscle, Cav1.2 is in cardiac muscle
In skeltal muscle Cav1.1 binds istelf to the SR via Ryr. This binding does not happen between Cav1.2 and Ryr, instead a little Ca comes in causing a calcium induced calcium release fromt eh SR which will initiate contractile phase of cardiac muscle
What happens to the length of teh A band and I band?
A band length stays the same and I band length shortens
How does relaxation occur?
- L-type Ca channel inactivates
- Phospholamban (PL) is phosphorylated, so that SERCA can pump Ca back into the SR
Ho does B adrengergic stimulation lead to relaxation
The B adrenergic receptor modulates the contractile response
cAMP levels are increased
protein kinases are activated
phosphorylation of phospholamban
phosphorylation of phospholamban permits Ca uptake by SR
this leads to relaxation
How does B adrenergic stimulation lead to enhanced contractile force?
- The B adrenergic receptor modulates the contractile response
- cAMP levels increased
- protein kinases activated
- phosphorylation of L-type Ca channel
- phosphorylation of L-type channel leads to increased Ca uptake into myocyte
- enhanced contractile force
what impact do the sympathetics have on the heart and great vessels?
increase HR positive chronotropic
what impact do the parasympathetics have on the heart and great vessels?
decrease HR and negative chronotropic
what is the vagal neurotransmitter and how does it work? what are the effects?
- the vagal neurotransmitter=achetychloine
- activates muscarinis AchRs that inturn, inhibit adenyl cyclase
- negatice chronotropism: via muscarinic AcHcRs in SA node (slowing of heart)
- Negative Inotropism: reduced contractile force (B-adrenergic antagonist)
The heart has regional histologic differences what the the different regions?
ventricular myocardium
atria, SA, AV nodes
Bundle of His
Cardiac fibroblasts
What are the atria, SA, AVnodes like histologically?
they are smaller CMs with fewer striations
- atrial myocytes have granules (G) with atrial natriuretic factor (ANF aka ANP)
- ANF is pleiotropic: vasodlation etc
*
WHat is the Bundle of His like histologically?
specialized for conduction
endotheln leads to cardiac myocyte leads to purkinje fiber
what are cardiac fibroblasts liek histologically?
- the hearts most abundant cell type
- but myocytes are much larger, hence occupy most of the hearts volume
What is the chronology of a heart attack?
- immediate: myocyte death (MB-CK and cTnI) (creatine kinase and troponin)
- +15 hours: inflammation
- +2-3 days: wound healing
- collagen deposition, leading to fibrosis
- +3-4 days: angiogenesis
- clinical enhancement via VEGF, FGF
- Scar deposition
What happens to cardiomyocytes during a heart attack?
cardiomyocytes die!
about 1 billion among a total of 5 billion (lose 20% of structure)
current research is looking into if the heart can regenerate!
WHat happens to CM turnover with age? how does it compare throughout the heart?
is decreases with age, <1% annualy
the rate of turnover is similar in all parts of the heart
What 7 cellulary therapies are thought to possibly regenerate the heart?
- skeletal muscle myoblasts
- cardiac fibroblasts (endogenous)
- pre-existing cardiomycytes
- adult stem cells (transplanted)
- bone marrow cells (transplanted)
- CMs from pluripotent stem cells (iPSCs)
Can skeletal myoblasts (skeletal muscle stem cells) re-muscularize the injured heart?
transplanted satellite cells cause arrhythma
Are Cardiac fibroblasts CM stem cells?
No
Fibroblasts respond to injury by making a scar
scars are permanent and they can’t contract
this is not good
Can pre-existing CMs proliferate to fix the heart?
Maybe
- adult CM proliferation can . be induced by
- inhibiting tumor supressors
- pro-proliferative agents
- phase 1 trials are planned to evaluate Neuregulin
Can endogenous adult stem cells re-muscularize the damaged heart?
apparently not, but can these cells can be induced?
- their existence is still controversial
- they might exist in ‘niches’ near BVs and/or in the epicardium
- they’re identified by a stem cell marker (c-kit)
what about transplanting c-kit cells?
phase 1 clinical trials isolate c kit cells from R atrium orIV septum via catheter and expand in culture. then transplant them. the result is that they function partly
what about transplanting bone marrow cells?
**ckit+ cells from bone marrow
no new muscle, no harm done. modest increase in heart function, but transient. the best bet would be to transplant MSCs
WHat about transplanting CMs from iPSCs?
the definitely do make beating CMs! but there are a few major concerns including tumor formation, CM immaturity, ability to integrate with host myocardium
the structural and molecular features of adult CMs confer heart function, which is aerobically powered by ______
mitochondria, lipids and vascularization
rhythmic heartbeat is conferred by ______
intercolated discs
how does excitation/contraction differ between skeletal and cardiac myocytes?
Ca channel subunits are different
CICR is unique to the heart
Localization of Ca channel proteins relative to SR is different
contraction is similar
In the heart ____________ are modulated via B-adrenergic, sympathetic and vagal pathways
strength of contraction, relaxation, and HR
What are the best options for regeneration of CMs in the diseased heart?
best options for re-muscularization:
- iPSC-CMs or new CMs from pre-existing CMs
