Arguing for Raised O-GlcNAcylation to be Closer to the Cause of Heart Failure than Thought

Researchers here use animal models to argue that raised levels of O-GlcNAcylation observed in heart failure patients are more important than thought as a contributing cause to the progression of this condition, rather than being further downstream as an end consequence. One must always be careful, however, in analysis of work where researchers break some important mechanism, causing problems, and then fix it. It is always possible to produce harm by causing unnatural disarray to a specific mechanism in animal metabolism. Removing that unnatural disarray will always help. That doesn't mean that the model necessarily has relevance to a condition in which the specific mechanism appears - relevance strongly depends on the specific details.

Proteins within living cells can be modified with the addition of small chemical groups that coax the proteins to change their shape or function. Among those modifications is O-GlcNAcylation, the addition of the sugar molecule O-GlcNAc (O-linked N-acetylglucosamine). The modification is controlled by two other molecules: O-GlcNAc transferase (OGT), an enzyme that adds the sugars to proteins, and O-GlcNAcase (OGA), an enzyme that facilitates their removal. Researchers have long known that proteins in the cells of people with heart failure have more O-GlcNAc than usual. But whether increased levels of the sugar were a cause or consequence of heart failure - or an attempt by the body to ward off heart failure - has been unclear.

Researchers genetically engineered mice with higher than usual levels of OGT or OGA in heart muscle cells. The animals with high OGT - and therefore more O-GlcNAc in these cells - developed severe heart failure. Their hearts began to weaken and pump less blood at just 6 weeks old. By 25 weeks of age, more than half of all mice with high OGT had died, while no control animals with normal levels of OGT had died. "These mice developed really stunning heart failure. Similar to many patients with cardiomyopathy, the mice developed enlarged hearts, abnormal electrical rhythms and died very early."

Animals with high OGA - and therefore lower than usual O-GlcNAc in their heart cells - remained healthy, however, and showed no signs of heart failure, even when challenged with an operation that constricts one of the heart's blood vessels. To test whether high levels of O-GlcNAc could be reversed to help prevent end-stage heart failure, the researchers next cross-bred the two strains of mice, engineering animals to have both high OGT and OGA levels. These animals no longer developed heart failure or died early, presumably because while OGT led them to add excessive O-GlcNAc sugars to proteins in the heart cells, the high levels of OGA reversed that excessive modification.

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/molecular-alteration-may-be-cause--not-consequence--of-heart-failure

Comments

Since I am a lay person, I can't say that I understand the details this article. I am wondering if supplementing with N-acetyl glucosamine increases the risk of O-GlcNAcylation? I have never seen that reported as a risk of N-acetyl glucosamine supplementation.

Posted by: Brad at May 20th, 2021 6:09 PM
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