Flashcards in Alterations in Myocardial Metabolism Deck (22)
Ischemia vs. hypoxia?
Ischemia: lack of blood flow
Hypoxia: lack of oxygen (theoretically, fuel could still be delivered and wastes removed)
What buffers ATP levels in cardiac myocytes?
What's the main regulator for the heart's use of fatty acids?
What metabolite inhibits CPT1?
Malonyl CoA, which is made by Acetyl CoA Carboxylase.
(if you have malonyl CoA around, the cell has broken down lots of fatty acids to acetyl CoA and doesn't need any more)
What effect to insulin and citrate have on CPT1?
Ultimately they downregulate it (by promoting the activity of Acetyl CoA Carboxylase, which make malonyl CoA, which inhibits CPT1)
What molecules increase CPT1 activity?
AMP (indicative of running out of ATP) and AMPK increase CPT1 activity.
They do so by inhibiting Acetyl CoA Carboxylase... so there's less malonyl CoA around to inhibit CPT1.
How is glucose transport different in fetal vs. adult cardiac myocytes?
Fetal: Glut1, insulin-independent glucose transport.
Adult: Glut4, insulin-dependent glucose transport.
Fetal hearts run mainly on glucose and lactate. Adult hearts prefer fatty acids (though they do like to use lactate generated by working skeletal muscle).
What effect does an increasing NADH/NAD ratio have on glycolysis? What happens to this in hypoxia?
High NADH/NAD ratio slows glycolysis.
In hypoxia, NADH builds up and must be used to make lactate so that glycolysis can continue.
What effect do NE and epi have on cardiac myocyte metabolism?
These hormones promote glycolysis and fatty acid oxidation (in constrast to insulin).
What's the role of myoglobin in cardiac myocytes?
Helps distribute O2 throughout the cell.
(also wides the PO2 gradient between blood and tissue)
What's the main consumer of ATP in working cardiac myocytes? (at least, the main consumer relevant to Ca++ levels)
SERCA - the Ca++ pump that moves Ca++ back into the SR.
What molecule regulates SERCA, and by what is that molecule regulated?
Phospholamban regulates SERCA.
It's regulated by phosphorylate, controlled by adrenergic/muscarinic inputs.
Aside from acting as an ATP reserve, what role does Creatine phosphate play?
By shuttling ATP from the mitochondria, it keeps ATP high in the cytosol, and low in the mitochondria.
How does the cardiac myocyte deal with transient ischemia?
There is "stunning."
There's acidosis, some slowing of Ox/Phos... a buildup of Ca++ in the cytosol.
This is somewhat protective, because it decreases cell's metabolic needs...
But, upon reperfusion, the Ca++ that has built up in mitochondria leads to oxygen free radical generation, which fucks shit up.
How can reperfusion cause apoptosis?
the generation of oxygen free radicals in Ca++ loaded mitochondira causes mitochondrial membrane damage -> Cytochrome C release -> apoptosis.
What does "hibernation" of ischemic myocytes refer to?
Myocytes can adapt to ischemia by reducing metabolism, and switching to more energy-efficient isoforms of contractile proteins, activating K+ channels to keep Ca++ low...
Hibernating myocytes do better with reperfusion.
How does the metabolism of cardiac myocytes change in hypertrophy?
There is increased lactate and glucose oxidation - the cells can actually start expressing fetal proteins.
How do dying myocytes promote fibrosis? What drugs can help stop this?
Dying myocytes -> A-II and TNF -> fibrosis.
ACE inhibitors and beta-blockers can help prevent this.
(beta-blockers help prevent high levels of Ca++ from building up)
4 different approaches to helping cardiac myocytes endure ischemia? (not reperfusion)
Inhibit fatty acid synthesis.
Improve Ca++ handling.
Inhibit fibrosis and apoptosis.
What can you do modify the metabolism of ischemic myocytes acutely?
Suppress fatty acid oxidation by giving glucose + insulin.
Also can give beta-oxidation inhibitors such as ranozidine and trimetazidine.
What enzyme can you target to mimic the effect of NO?
Inhibiting PDE5 slows the breakdown of cGMP (the 2nd signaling molecule for NO).