Targeting Macrophage Metabolism to Treat Atherosclerosis

Researchers here propose enhancing the cellular operation of the immune cells called macrophages in order to slow the progression of atherosclerosis, a condition in which blood vessel walls become inflamed and damaged, and dangerous fatty plaques grow inside the blood vessels. A number of processes contribute to the progression of atherosclerosis once any initial damage to blood vessel walls exists, and one of the important ones is the behavior of macrophages at the site of damage. These cells are drawn by the presence of oxidatively damaged cholesterol and lipids, ingest them and break them down. Some are overwhelmed by the volume of these damaged molecules, however, becoming what are called foam cells. Many die and their debris contributes to inflammation, and the growth of plaques that narrow blood vessels. This attracts further macrophages in a vicious cycle that ends in disaster when a plaque breaks free and blocks a blood vessel to cause a stroke or heart attack. This research is focused on enhancing the ability of macrophages to deal with cholesterol:

Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways.

In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1-mediated cholesterol efflux. Specifically, anti-miR33 derepressed the novel target genes PGC-1α, PDK4, and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe−/− mice with anti-miR33 oligonucleotides reduced aortic sinus lesion area compared with controls, despite no changes in high-density lipoprotein cholesterol or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared with normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1α, SLC25A25, NRF1, and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans.

This study demonstrates that anti-miR33 therapy derepresses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis.

Link: http://dx.doi.org/10.1161/CIRCRESAHA.117.305624

Comments

The SENS approach (as we all know) involves getting a new enzyme to the macrophage lysosomes to 'digest' the oxidised LDL.

Would a gene therapy be the best way to deliver these new enzymes?

Posted by: Jim at December 17th, 2015 12:15 PM

The introduction to the article is already way above my ahead. I am only a beginner in biology. So I will focus right now in getting the defintions of the terms microphages and atherosclerosis into my head and look into the terms a bit on Wikipedia, as the auhor kindly took the time to include a link to Wikipedia. Once I have those terms down, I think that I can wrap my mind better around the stages in which atherosclerosis progresses. Once that is understood, I can move on to the article. I am merely saying that this is somewhat advanced for me as a beginner, but I like challenges. I can do this.

Posted by: Plato at December 17th, 2015 4:09 PM

What I understand so far about macrophages (after reading the Wikipedia page's definition): microphages are white blood cells (WBCs) that digest junk. Atherosclerosis is a condition that involves WBCs. Something goes wrong, which produces plaques (whatever that means). I am going to look into what plaque means next, but I just wanted to write down my thought process as I am trying to understand the article.

Posted by: Plato at December 17th, 2015 4:19 PM

So when something goes wrong with the WBCs called macrophages ("big eaters") in the condition called atherosclerosis, it produces junk which logically mostly consists of macrophages. I get what fatty plaque means now. At least I hope I do.

Posted by: Plato at December 17th, 2015 4:23 PM

@Jim - Thank you so much for pointing this video out to me! You have no idea how helpful it is to me. Seeing the whole thing in animation makes the information about the biological structures and processes come to life.

Posted by: Plato at December 17th, 2015 5:42 PM

@Jim: How would you deliver them, then?

Posted by: Antonio at December 17th, 2015 5:49 PM

@Plato: I'm curious... how did you know about this blog?

Have you tried the introductory articles in the right side? --->

Posted by: Antonio at December 17th, 2015 5:53 PM

@Antonio - When reading around about gene therapy and it's use in allotopic expression of mitochondrial DNA I see that CRISPR is now deliverable via AAV.

http://www.the-scientist.com/?articles.view/articleNo/42580/title/Enzyme-Improves-CRISPR/
http://www.nature.com/nature/journal/v520/n7546/full/nature14299.html

I'm feeling more hopeful than yesterday. Gene therapy is well funded, so it will hopefully happen, and in fairly short order. That nature article abstract said:

"Within one week of injection, we observed >40% gene modification, accompanied by significant reductions in serum Pcsk9 and total cholesterol levels."

Since I can't see behind the paywall I'm assuming that means 40% of liver cells were genetically edited.

Posted by: Jim at December 17th, 2015 7:54 PM

Ex vivo gene therapy to modify and expand wbc would in my view be the way to do it.you could even filter out the cells and replace with modified ones to conserve the biological "capacity"

Posted by: Steve h at December 18th, 2015 1:27 AM

@Jim: Very encouraging news.

Posted by: Antonio at December 18th, 2015 2:01 AM

@Antonio - I found this site by googling. Thank you for your kind suggestion. Yes, I have already read a couple of those articles. I have not read all of them yet. I am still quite ignorant in the field of biology. So I may not be able to comprehend everything said in those articles either. Still, I want to learn. I have to start somewhere. I try to combine reading the recent and introductory articles. It helps me to stay focused. What us important now is that I comprehend, focus, and memorise. I am very grateful when people make kind suggestions and help out a beginner like me. I am often still quite confused, intimidated, and surprised by all the information that is totally novel to me.

Posted by: Plato at December 18th, 2015 4:16 AM

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