Longevity Briefs: How Blood Vessel Fat Drives Heart Disease

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Cardiometabolic disease is a dangerous condition involving of some combination of high blood pressure and metabolic disturbances such as high blood sugar or blood triglycerides (fat). This creates a perfect storm that damages the lining of the blood vessels (known as the endothelium), resulting in inflammation that drives the growth of fatty plaques (atherosclerosis). These fatty plaques narrow the arteries, eventually leading to potentially fatal cardiovascular events like heart attacks. Another effect of damage to the endothelium is that it hinders the relaxation and dilation of blood vessels. This is because it is the endothelium that is responsible for releasing nitric oxide (NO), the signal that ‘tells’ the muscles within the walls of the blood vessel to relax. These processes are inevitable with advancing age, but metabolic conditions like diabetes dramatically accelerate them.

Blood vessels are wrapped in a protective layer of fat called perivascular (‘peri-‘ meaning ‘around’ and vascular meaning blood vessels, so ‘around the blood vessels’) adipose tissue (another name for fat tissue). Perivascular adipose tissue, or PVAT, has long been suspected of contributing to cardiometabolic diseases when it experiences metabolic disruptions. However, there hasn’t been a clear mechanism to explain how the dysfunction of PVAT would lead to dysfunction of the blood vessel. In this study, researchers uncover the missing link (and a potential drug target) in a series of human and mouse experiments.

The discovery:

First, researchers looked at 27 people with obesity and hypertension who were already showing features of accelerated vascular ageing. Small arteries dissected from fat during surgery were compared to samples from 13 healthy controls. As expected, the diseased vessels had lower nitric oxide signalling resulting in weakened relaxation, as well as significantly higher inflammatory gene activity compared to the controls.

The researchers hypothesised that BET proteins (Bromodomain and Extra-Terminal motif proteins) could be partly responsible. BET proteins are a group of molecules that bind to histones (proteins around which the DNA is coiled) in order to enable chromatin remodelling – a process in which regions of DNA transition between a ‘packed’ state in which they are inaccessible, and an ‘unpacked’ state in which associated genes are available to be read. Previous studies using recently developed BET inhibitors had shown that BET proteins increased cellular stress, inflammation and disease. In the present study, exposing diseased vessels to the BET inhibitor RVX-208 significantly improved relaxation responses, increased nitric oxide production and reduced inflammatory gene expression.

Researchers then tested what would happen if PVAT was stripped from the blood vessels. They found that in vessels from healthy controls, PVAT improved vessel behaviour, while the reverse was true in diseased vessels – PVAT appeared to be contributing to vessel dysfunction. However, RVX-208 reversed this dysfunction to a far greater extent in diseased vessels in which PVAT was present. This suggested that PVAT had switched to a behaviour in which it became harmful to vessel function in people with cardiometabolic disease, and that BET was central to this relationship.

To truly put this idea to the test, researchers then looked at the effects of RVX-208 in 15 week old mice fed a high-fat diet. They found that without significantly affecting body weight, RVX-208 reduced stiffness of the aorta, improved endothelial function and reduced inflammatory signalling in PVAT. Further investigation of the mechanism suggested that the main gene being suppressed as a result of BET inhibition was the gene for hexokinase-2 (HK2). HK2 is an enzyme involved in glycolysis, the first stage of glucose (sugar) consumption by cells. Essentially, inhibiting BET using RVX-208 was forcing PVAT to burn less sugar and switch to fat metabolism instead. Glycolysis releases energy more rapidly and also produces byproducts that favour inflammation, so suppressing glycolysis also suppressed inflammation within PVAT. Finally, researchers demonstrated that suppressing HK2 also improved vessel relaxation in human arteries from cardiometabolic patients. This effect was much larger when PVAT was still attached, providing a proof of concept that HK2 might be targeted to improve cardiovascular health.

The implications:

This research suggests that the ‘metabolic program’ adopted by the fat wrapped around blood vessels plays an important role in vessel health. In cardiometabolic disease, PVAT over-relies on glucose for its energy, resulting in inflammation that ‘spills over’ into the endothelium. HK2 appears to be a key regulator of this increased glycolysis, which can be reversed by suppressing HK2.

Some clinical trials are already underway for the use of BET inhibitors in the treatment of cardiovascular diseases. This study suggests that targeting the HK2 enzyme specifically could also be an option. It also demonstrates that perivascular adipose tissue is more than passive cushioning for the blood vessels – its metabolic health can have an impact on blood vessel function. The practical takeaway is nothing new, but worth reiterating: maintaining good metabolic health is essential for preventing cardiovascular disease and most likely delays vascular ageing. Maintaining a healthy weight, consuming a balanced diet (ideally one focussed on plants) and getting adequate physical exercise and sleep can all help maintain metabolic health into old age.