Neuronal form of globin prevents heart attack and stroke damage

10 November 2006

Scientists have discovered that overexpression of a globin molecule normally found in the brain substantially reduces damage to both cardiac and cerebral tissue in animal models of myocardial and focal cerebral ischemia.

The findings suggest that therapies to stimulate production of the protein – called neuroglobin – could be used in humans to protect against ischemic cardiac and neuronal injury during myocardial infarctions and strokes, respectively.

Neuroglobin has significant homology with myoglobin and hemoglobin, and is predominantly expressed in the brain. The research team, from the Buck Institute in Novato, California, and led by David Greenberg, have been studying neuroglobin's potential healing role in stroke for a number of years.

Speaking to MedWire News, lead author of the current study Adil Khan explained that this previous research showed that neuroglobin levels increase in stroke.

Having found that intracerebral delivery of neuroglobin DNA in mice could protect against damage from cerebral ischemia, the team developed transgenic mice overexpressing neuroglobin to study its potential protective function further.

The transgenic mice, which displayed no obvious phenotypic abnormalities, not only had increased levels of neuroglobin in the brain, but also had clearly detectable levels of the protein in heart tissue.

The researchers then induced myocardial and focal cerebral ischemia in both the transgenic neuroblobin-expressing mice and control mice.

The results showed that the volume of cerebral infarcts was reduced by around 30% in the neuroglobin transgenic mice compared with controls.

Furthermore, the protective effect of neuroglobin was also seen in the heart, with an approximately 25% smaller myocardial infarct volume in the transgenic versus control mice.

Exploring how this cardioprotective effect might occur, Khan and team noted that the neuroglobin in myocardial tissue of transgenic mice was found predominantly in endothelial cells.

The production of nitric oxide (NO) by endothelial NO synthase (eNOS) is an established mechanism for endothelium-mediated vasodilation and protection against cerebral and myocardial ischemia.

The researchers therefore examined the expression of eNOS in myocardial tissue from the mice, and found markedly increased levels of eNOS were evident in both myocardial sections and cell lysates form the neuroglobin transgenic mice compared with control mice.

Khan said that a key area of the team's future research will be to further define the mechanism underlying the relationship between elevated neuroglobin and eNOS.

Noting that, for cardiologists, the idea that a neuronal protein may have a role to play in endothelial-dependent vasodilation may seem strange, he added that the team also intends to investigate whether neuroglobin has a direct effect in making cells more resistant to dying and if so, what the mechanisms involved are.

"There may be death mechanisms that not only exist in muscle cells, but also in neuronal cells and possibly even all other cell types; they may share common pathway," he said.

These mechanisms might be amenable to pharmacologic intervention, and Khan pointed out that there is a possibility of "naturally" modulating levels of neuroglobin, as already achieved with other globins – for example the increased production of hemoglobin by dietary iron supplementation.

"If there are ways to naturally manipulate the levels of other globins, there might also be ways to naturally modulate neuroglobin that could provide protection," he said.

The findings appear early online in the Proceedings of the National Academy of Sciences.

Proc Natl Acad Sci 2006; Advance online publication