Damaged cells could be sending out signals that provoke an immune response that leads to hypertension, potentially opening up a new way of approaching blood pressure control, Augusta University researchers said. The work will be funded by a large comprehensive grant that will allow them to approach it in different ways.
The university recently received a $9.4 million program project grant from the National Heart, Lung and Blood Institute to fund three related projects looking at the impact of what are called damage-associated molecular patterns, or DAMPs. The AU group has been working in that field since 2011 but finally was able to get the big comprehensive grant, said Dr. Clinton Webb, chair of the Department of Physiology and a principal investigator on the grant.
“It just took a long time to get it funded,” he said.
The large grants are becoming increasingly difficult to get – a search of National Institutes of Health records found that the NHLBI only awarded two new ones in Fiscal Year 2015, the most recent records available. The project has also benefited from increasing evidence of DAMPs in important chronic disease processes, such as diabetes.
“You see more and more grants address this hypothesis,” Webb said. There is also growing consensus that the immune system and inflammation are playing a role in high blood pressure and heart disease, said Dr. Jennifer Sullivan, a cardiovascular physiologist.
“We developed that story as a scientific community pretty well,” she said. “But then it was time to take a step back. OK, we know this inflammation happens, we know these cells are activated but what is causing it? Really, that’s what we are addressing here.”
There are three major projects within the grant. One is looking at whether hypertension causes increased cell death within the walls of blood vessels, releasing mitochondria, the powerhouse of cells, which triggers receptors linked to inflammation.
Mitochondria are thought to trigger the part of the immune system that defends the body from bacteria, and Webb has already shown that blocking a similar receptor in the same rat model of hypertension lowers blood pressure. Another project is focusing on the kidney, a vital organ for controlling blood pressure, and a crucial area within the kidney that helps to concentrate urine but also tends to become clogged with red blood cells because of their long looped shape, said Dr. Paul O’Connor, a renal physiologist.
The long thin vessels are lined with cells that O’Connor believes contract and help move along red blood cells. Acute injury to the kidney can impair their function and cause the vessels to become clogged with red blood cells, but O’Connor suspects the same thing can happen over time with low-level damage.
“Looking at this acute effect, where there’s lots of injury, does it occur chronically at a very low level and can that lead to changes in kidney function that promote high blood pressure?” he said.
Another project is focusing on a protein called high mobility group box 1 or HMGB1, a protein that in the nucleus of the cells is important for DNA regulation but outside the cells is thought to interact with well-known receptors for inflammation. It has been implicated in some other diseases, such as lupus, and that work makes it easier to study it in hypertension, Sullivan said.
“It makes some of our work easier,” Sullivan said. “It makes it a nice target. There are already drugs that they know that can manipulate it, there are antibodies (to it.) So now applying it to this disease, we have some of those tools available to test our hypotheses more directly.”
And that provides the potential to find a better therapy than current drugs, which treat symptoms, by getting at the root causes, she said.
“(To) get more at initiating events so maybe we will get a more specific type of target that you can develop more effective drugs to use for the treatment of hypertension,” Sullivan said.
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