Many of the 75 million Americans with essential hypertension also develop diabetes and other complications in addition to their high blood pressure, and researchers have discovered a common molecular mechanism in a strain of rat that explains why such metabolic disorders arise together in mammals.
The bioengineering researchers at UC San Diego's Jacobs School of Engineering also showed that a drug developed for unrelated purposes in humans was effective in counteracting the underlying molecular mechanism in the spontaneously hypertensive rat (SHR), a strain predisposed to develop high blood pressure.
In a paper published June 30 in the online version of Hypertension, Frank DeLano, a research scientist at UC San Diego, and Geert Schmid-Schönbein, a professor of bioengineering, describe how they successfully reversed the SHR animals' symptoms of high blood pressure, a pre-diabetes condition called insulin resistance, and immune suppression.
H. Glenn Bohlen, a professor in the Department of Cellular and Integrative Physiology at Indiana University Medical School, wrote in an accompanying editorial in Hypertension that the new study will likely be important to people suffering from obesity as well as hypertension. "With the national and international emphasis on obesity and its attendant cardiovascular problems, there is a tendency to forget that essential hypertension affects about the same percentage of humans as does serious obesity and an even higher percentage of the population than does type 2 diabetes mellitus," wrote Bohlen. "The elegant study by Delano and Schmid-Schönbein points to a potentially very important overlap of an insulin resistance mechanism with hypertension in the spontaneously hypertensive rat (SHR)."
The SHR strain is a model for essential hypertension in humans because both the rodent and many humans with hypertension also develop a variety of other metabolic complications when high blood pressure strikes.
In the circulation of SHR rodents, Schmid-Schönbein and DeLano found significant levels of proteases, which are enzymes that break down proteins. Natural enzyme inhibitors found in normal healthy rats did not lower the level of protease activity in the SHR strain to normal levels.
"We were looking for a common cause of diverse but concurrent metabolic problems and we were testing our theory that enhanced proteolytic activity in the circulation may be the root cause," said Schmid-Schönbein. "In the hypertensive rat we studied, enzymes cleave extracellular portions of several protein receptors, such as the insulin receptor, so that insulin can no longer bind and facilitate normal metabolism of glucose."
Under normal conditions, the pancreas releases insulin in the bloodstream. The molecule then binds to insulin receptors on the cell-surface membrane, which signals the cells to absorb glucose, a main source of cellular energy. However, when a cell loses the binding site for insulin on the insulin receptors, it becomes "resistant," or unresponsive to insulin and no longer absorbs glucose in healthy amounts on cue, which is the problem in type 2 diabetes.
The researchers showed that the SHR animals have protease activity in their circulation that cleaves more than just insulin receptors. In these animals, proteases also cleave significant numbers of CD18, an important binding receptor on the surface of infection-fighting leukocytes. CD18 gives these cells the ability to adhere to the walls of blood vessels as a way to home in on infections. With the loss of CD18 receptors, leukocytes of the SHR animals are unable to bind to the wall of blood vessels, resulting in a compromised immune system.
"These results point to a single mechanism that explains multiple and diverse cell dysfunctions encountered in hypertensive rats, and they also suggest that a similar mechanism may be operating in humans suffering simultaneously from hypertension, diabetes, and other metabolic conditions," said Schmid-Schönbein.