Molecule limits heart attack damage in mice

"Heart attack drug may reduce tissue damage," says the BBC.

This headline was based on new research in mice. The research showed that a molecule called MitoSNO may be able to reduce the tissue damage that can occur after a heart attack.

The heart pumps oxygen-rich blood around the body, but it also needs its own oxygen supply to function properly. When a person has a heart attack, the blood supply to the heart becomes blocked, starving areas of heart tissue of oxygen.

This can cause damage to the heart muscles and, in many cases, can result in heart failure (where the heart struggles to meet the body’s demand for oxygen). Previous research has found that some of the damage to the heart is caused by chemicals called reactive oxygen species (ROSs). ROSs damage the heart and also inhibit the body’s ability to repair damaged heart tissue.

In this new study, researchers injected MitoSNO into mice after an induced heart attack. The MitoSNO was injected as the blood was returning to the heart. Doing this stopped such high levels of ROSs being produced and protected a greater proportion of the heart tissue from damage than a control treatment.

While this research is still in its early stages, understanding and harnessing the protective effect of MitoSNO appears to provide an avenue for future research to investigate new ways to protect the heart from damage after a heart attack.

Where did the story come from?

The study was carried out by a collaboration of researchers from institutions in the UK, New Zealand and the US. It was funded by organisations from these three countries.

The research publication states a conflict of financial interest as two of the study authors hold an EU patent on the technology described in this publication.

It was published in the peer-reviewed journal Nature Medicine.

The BBC coverage of the research was accurate and well-balanced.

What kind of research was this?

This was laboratory-based research using mice to investigate new ways to help repair heart tissue after it has been starved of oxygen.

When a person has coronary (ischaemic) heart disease some of the blood vessels are clogged up by fatty deposits. If the supply of blood is restricted it can cause a type of chest pain, known as angina, which is often triggered by physical activity.

If the supply of blood to the heart becomes completely blocked it starves the muscles and tissues of the heart of oxygen, which results in a heart attack. Without oxygen, areas of heart tissue start to die, leading to potentially life-threatening damage.

To treat coronary heart disease, doctors attempt to unblock the blood vessels and restart the blood supply to the heart as soon as possible. However, even if this is successful, as the blood re-enters the damaged heart muscle, the oxygen-starved cells start to release high levels of chemicals called reactive oxygen species (ROSs). This causes damage to the heart cells themselves and surrounding heart tissue. This means that although the blood supply has been restored to the heart, damage still occurs and the heart tissue may not recover fully.

ROSs are thought to be produced by a cell structure called the mitochondria. Cells in the mitochondria act like tiny batteries, producing the energy cells need to function.

This new research investigated ways to target the mitochondria during the initial stages of restarting the blood flow to the heart, to stop the high levels of ROSs being produced, so the heart could repair itself more fully.

What did the research involve?

The research investigated the effects of a molecule called mitochondria-selective S-nitrosating agent, MitoSNO, in reducing the production of ROSs in the mitochondria of recovering mouse heart tissue.

The researchers created an artificial model of a heart attack using mice. They blocked one of the mice’s main blood vessels to the heart for 30 minutes, starving the heart tissue of oxygen. This was followed by 120 minutes of ‘reperfusion’ (where blood flow to the heart was re-established).

The researchers injected some mice with MitoSNO just before reperfusion started. In one experiment, they tracked the location of the injected MitoSNO molecules to see if they targeted the mitochondria. In a second experiment, the researchers measured the protective effect of MitoSNO on tissue damage caused by the heart attack. In a third experiment, they injected MitoSNO 10 minutes after reperfusion had started to see if it had any protective effect, and to see how important the timing of the injection was.

A further series of experiments was undertaken to attempt to uncover the exact mechanism by which MitoSNO was having its protective effect on the recovering heart tissue.

What were the basic results?

As the researchers expected, the study found that the MitoSNO travelled to the mitochondria when injected. Their main finding, however, was that injecting MitoSNO at the start of reperfusion helped protect against damage associated with reperfusion. They measured this protection as the percentage of damaged tissue in a specific zone of the heart. Around 30% of the target heart tissue was damaged in mice not receiving MitoSNO, but only 10% in mice that did receive MitoSNO.

The researchers were able to establish that the protective effect was due to MitoSNO interacting with a molecule called mitochondrial complex I. This interaction slowed the reactivation of the mitochondria during the first few minutes of the reperfusion, thereby decreasing the harmful ROS production.

Interestingly, it appeared that MitoSNO would only work if injected at the start of reperfusion, later injection of the molecule did not protect the heart, so timing appeared to be very important.

How did the researchers interpret the results?

The researchers concluded that their results, “identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy”.

In lay terms, they say that MitoSNO may offer the potential to be a useful treatment if given in the immediate aftermath of a heart attack.

Conclusion

This laboratory-based research in mice, which used a simulation designed to mimic the effects of a heart attack, appears to show that the molecule MitoSNO can prevent some of the heart tissue damage of a heart attack and the consequences of the return of blood to the heart (reperfusion).

It is important to remember this was a small, early study in mice. Further studies in rodents would be needed to confirm these initial findings as true and accurate.

Furthermore, this study was carried out in mice and the results may not be the same for people. Research in humans would be needed to understand fully the human biological processes involved and to establish whether MitoSNO is effective or safe when used in a similar way for real people. These experiments would need to include a rigorous assessment of the safety of the molecule.

Despite the limitations, this intriguing research does highlight a potential biological target for further research. Ultimately, researchers hope to harness the protective effects of MitoSNO to reduce the damage in, and therefore aid the recovery of, people who have recently suffered heart failure due to lack of oxygen.

Heart failure can have a significant adverse impact on quality of life so any treatment that can prevent or repair damage to the heart would be very valuable.