Vidyya Medical News Service
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Volume 6 Issue 116 Published - 14:00 UTC 08:00 EST 25-Apr-2004 Next Update - 14:00 UTC 08:00 EST 26-Apr-2004
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Inflammation, hypertension are focus of major new MCG research program

Understanding the relationship between small proteins that regulate inflammation and the big problem of hypertension is the focus of a major new research program at the Medical College of Georgia. An $11 million, five-year grant from the National Heart, Lung and Blood Institute of the National Institutes of Health will help MCG researchers determine if there is a direct cause-and-effect relationship between the two, a finding that could open the door for a new approach to treating hypertension.

"We know there is a correlation between low levels of pro-inflammatory mediators, called cytokines, and high blood pressure," said Dr. R. Clinton Webb, chair of the MCG Department of Physiology and principal investigator on the new NIH Program Project grant. "But we want to know what role these cytokines play in blood pressure elevation and hypertension."

The result could be new, direct targets for treating high blood pressure, a problem that the American Heart Association says affects one in four American adults and is a major risk factor for heart disease.

The first link between inflammatory mediators and heart attacks came with a study published in 1997 in the New England Journal of Medicine by Harvard University's Dr. Paul Ridker correlating higher levels of one element of the inflammatory cascade - the increasingly well-known C-reactive protein - with heart attacks. More recently, Dr. Ridker's group found that higher blood levels of the mediator interleukin-6 - which goes up in inflammation and actually stimulates C-reactive protein - correlates with higher blood pressure. Many physicians now prescribe a daily baby aspirin for those concerned about heart disease and have begun testing C-reactive protein levels to help predict a patient's risk for heart attack.

"Right now, there is a lot of correlation if you look at the literature between C-reactive proteins, interleukin-6, correlations between a lot of inflammatory markers and cardiovascular disease, blood pressure and myocardial infarction," said Dr. Mike Brands, MCG cardiovascular-renal physiologist and a project leader on the new grant. "These things correlate, but there is really not good, direct, cause-and-effect evidence saying that these things cause hypertension, cause cardiovascular disease. There really has not been a comprehensive program to study that. That's what led to this," Dr. Brands said of the collaborative study that pools the talents of MCG faculty in the Department of Physiology and the Vascular Biology Center.

"The easiest thing to do for cytokine elevation is to give somebody an aspirin," Dr. Webb explained. "That will bring cytokines down and that's really what Dr. Ridker showed. But aspirin doesn't cure hypertension. People take aspirin and it doesn't do much for their blood pressure. We just don't know what the cytokine involvement is and that is what we want to know. Cytokines could be involved just in the end-organ injury that occurs in hypertension and have nothing to do with blood pressure regulation itself."

So the researchers are dissecting the relationship from different angles, from the psychosocial stresses that can elevate pressure to events within blood vessel walls that can keep it elevated.

Dr. Brands' is using the male mouse's territorial instincts to look at whether interleukin-6 is necessary for blood pressure to go up during stress. "It's the first data we have suggesting that cytokines are important," he said of the mouse model for stress in which they have compared blood pressure responses in a normal mouse to one missing the interleukin-6 gene. When Dr. Dexter Lee, a postdoctoral fellow working with Dr. Brands, puts a male mouse in a cage where another male has been for a few days, territorial instincts rev up, adrenaline likely goes up and blood pressure does as well. In that situation, the blood pressure does not go up as much in the knockout mouse.

To explore the response of the kidneys, which regulate sodium and water volume in the body and are a major regulator of blood pressure, Dr. David Pollock, a physiologist and project leader, is looking at the evidence that cytokines stimulate endothelin production.

Endothelin, a potent substance that comes from the endothelial cells that line blood vessels, is a good guy and a bad guy, Dr. Pollock said. "Normally in a healthy person's kidney it's a good guy because it relaxes blood vessels and helps you get rid of salt. But in salt-sensitive hypertension, in other words animal models that get hypertensive when you put them on a high-salt diet, there seems to be a defect in that pathway," he said. When that pathway is defective and cytokines stimulate even more endothelin, endothelin's bad side predominates: decreased ability to relax blood vessels, decreased blood flow, decreased salt excretion, less oxygen for tissues and destructive changes in blood vessel walls. "The protective part goes away and now you have all the bad part of the endothelin pathway activated," said Dr. Jennifer Pollock, biochemist and the biochemistry core leader on the grant.

Dr. John D. Imig, renal vascular biologist, and Dr. Edward W. Inscho, physiologist, who are both project leaders, are looking at signaling mechanisms that effect kidney response.

"We think the elevation of cytokines that occurs in cardiovascular disease is actually decreasing metabolites produced by the endothelium that would be anti-inflammatory and have protective effects to the vasculature," Dr. Imig said. He believes that cytokines, such as interleukin-6, decrease arachidonic acid metabolites, thereby reducing the ability of these fatty acids inside cell membranes to relax smooth muscles, increase blood flow and reduce inflammation.

Dr. Inscho is piecing together the roles of interleukin-6 as well as the cytokines TNF- and TGF- in the problems that occur in the microvasculature of kidneys in hypertension.

"We have been interested in the hypertension angle because we know blood vessels in the kidney don't function correctly; they also don't function correctly in diabetes. These two diseases are major players for kidney damage and it's a huge problem in Western society today," Dr. Inscho said. "Our studies are designed to look at how the kidney controls its blood flow, why it's broken in hypertension and whether or not we can make the case these agents are involved."

Dr. Webb is looking at what role these agents or cytokines may play at the basic level of the smooth muscle cells that comprise blood vessel walls inside the kidney. "In hypertension, blood vessels are over-constricted and I am interested in the constrictor mechanisms," he said.

He will test his hypothesis that angiotensin II, a blood vessel constrictor released by the kidneys, makes blood pressure start to rise by producing the oxygen-free radical, superoxide, and keeps the blood pressure up by inducing expression of the inflammatory mediator, interleukin-6, inside the blood vessel wall.

Superoxide and interleukin-6 increase levels of the enzyme, Rho-kinase, which Dr. Webb and his colleagues have found has an important role in the body's ability to maintain an elevated blood pressure; in fact, Rho-kinase seems to have a larger role in contractility in hypertension than when pressures are normal.

"Hypertension is not a single gene defect," Dr. David Pollock said. "It's a disease that is very complex and involves a lot of genes that interact. You listen to these pharmacogenetics experts and they tell you your gene information is going to be imprinted on a credit card one day and it's going to tell you whether you secrete too much interleukin-6 or something like it and that you need a specific combination of medications based on your profile. One of those might be an inhibitor of the cytokine pathway. That is sort of the dream world right now, but it could be the reality some day."



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