Blocking a Specific Epigenetic Enzyme Could Prevent Diabetic-Related Heart Failure

Researchers investigate whether inhibiting HDAC3 will halt the progression of diabetic cardiomyopathy

Heart Epigenetics and Diabetes

Heart disease has been singled out as the leading cause of death among people with diabetes. It’s estimated that 68 percent of diabetics age 65 or older will die from some form of cardiovascular disease. Coronary atherosclerosis, or hardening of the arteries, is the most prevalent of these diseases, but there is another very common heart condition specific to diabetes that has been getting more attention in recent years. It’s called diabetic cardiomyopathy (DCM) and it’s independent of coronary artery disease and hypertension. What’s more is it’s usually not detected early enough before irreversible damage is done to the heart.

Now researchers in China have discovered that a specific epigenetic enzyme may be responsible for the progression of DCM.  They explored whether blocking the enzyme could prevent this diabetes-induced cardiac dysfunction from occurring. Their findings were recently published in the July issue of Clinical Science.

DCM can be described basically as advancing damage to the structure and function of the heart muscle caused by having diabetes. Over time, the damage renders the heart incapable of circulating blood effectively throughout the body and eventually leads to heart failure. The condition is usually asymptomatic, so most diabetics don’t know that they have DCM until it’s progressed for some time. There’s no proven effective treatment for this disorder right now, but detection is possible. Preventing the progression of damage is the best option for patients diagnosed with DCM. Various anti-diabetic and anti-hypertension agents have been used with some success, but they are not specific to DCM. This may be because the underlying molecular mechanisms involved in the development of this disease are still not entirely known.

Prior studies have indicated that histone deacetylases (HDACs) are associated with DCM. However, only total HDAC inhibition has been investigated on certain mouse models. This study focused particularly on HDAC3 due to its association with heart failure, hypertrophy, and aberrant energy metabolism. The researchers sought to determine if HDAC3 inhibition could delay the development of DCM and further to elucidate the epigenetic mechanisms involved in the process.

HDACs are a class of enzymes that remove histone acetyl epigenetic modifications, thus allowing DNA to condense around histones and shut off gene expression. HDAC inhibitors are already known as potential anticancer agents, plus they’ve been used to treat many other diseases as well. In previous articles, we have discussed how certain HDAC inhibitors (HDACi) have been used to treat kidney damage and lung cancer, and how a naturally derived HDACi can potentially fight bladder cancer.

The researchers tested their theory by administering a selective HDAC3i drug (RGFP966), a total HDACi drug (VPA), or control solution to groups of spontaneously developed type-1 diabetic mice and wild-type mice for three months. The main findings from the study revealed that the HDAC3 inhibitor significantly reduced HDAC3 and total HDAC activities, yet did not affect blood glucose levels. It essentially prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis, as well as reduced cardiac oxidative stress, insulin resistance and inflammation. Even more impressive was that the experimental effects were still seen months after administration of the drug was discontinued.

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The researchers reported, “The cardiac protection by inhibition of HDAC3 from DCM is persistent at least for 3 months after the end of treatment, like a ‘protective memory’ phenomenon.” This occurrence, they believe, is very much like “metabolic memory” which has been observed in diabetics who practice intensified glycemic control and then benefit from the sustained effects well after they’ve returned to a more typical management of their glucose.

To determine the mechanisms by which inhibition of HDAC3 produced this cardioprotection, the researchers investigated the expression levels of ERK1/2, a signalling molecule that is known to stimulate cardiac hypertrophy. They found that the HDAC3i treatment blocked ERK1/2 activation in nucleus by epigenetically regulating DUSP5 via histone H3 acetylation in the hearts of the type-1 diabetic mice.

Using a microplate-based ChIP assay from EpiGentek, the researchers were able to demonstrate that HDAC3 inhibition raised histone H3 acetylation on the DUSP5 gene promoter at 3 and 6 months. They also noted in their report that, “HDAC3 inhibition-mediated stimulation of insulin intracellular signalings and the activation of AMPK may also have certain contributions.”

This study was the first to look individually at HDAC3 inhibition and some limitations remain. Therefore, further research is needed to determine the exact mechanisms involved that influence the development of DCM. Nonetheless, the data does suggest that targeting HDAC3 and the DUSP5-ERK1/2 pathway that epigenetically regulates it could increase our knowledge of this complex disorder and potentially lead to effective treatments that someday prevent DCM.

Diabetes is a disease that can be monitored and managed. However, there are complications that can develop over time. DCM is a condition that could go unnoticed and permanently damage the heart. Early detection and appropriate treatment could prevent the worsening of this condition to overt heart failure. Studies such as this to find therapies that can stop this cardiac condition from progressing are much needed, especially as diabetes continues to be a growing global health problem.

 

Source: Xu Z et. al. (August 2017). Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathwayClin Sci (Lond). 131(15):1841-1857.

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  • Carolyn

    Bad heart failure. I was diagnosed with type 2 Diabetes and put on Metformin on June 26th, 2016. I started the ADA diet and followed it 100% for a few weeks and could not get my blood sugar to go below 140. Finally i began to panic and called my doctor, he told me to get used to it. He said I would be on metformin my whole life and eventually insulin. At that point i knew something wasn’t right and began to do a lot of research. Then I found Lisa’s diabetes story (google ” HOW EVER I FREED MYSELF FROM THE DIABETES ” ) I read that article from end to end because everything the writer was saying made absolute sense. I started the diet that day and the next morning my blood sugar was down to 100 and now i have a fasting blood sugar between Mid 70’s and the 80’s. My doctor took me off the metformin after just three week of being on this lifestyle change. I have lost over 30 pounds and 6+ inches around my waist in a month. The truth is we can get off the drugs and help myself by trying natural methods

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