In the circulation of SHR rodents, Schmid-Schnbein 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-Schnbein. 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 simulta
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University of California - San Diego