Anti-inflammatory properties of glycosaminoglycans in myocardial injury.

Reperfusion of the ischemic myocardium results in irreversible tissue injury, leading to decreased cardiac performance. While early reperfusion of the heart is essential in preventing further tissue damage due to ischemia, reperfusion can expedite the death of vulnerable, but still viable, myocardial tissue because of a local inflammatory response. Modulating inflammation, therefore, is a potential pharmacological target to protect the heart from reperfusion injury. The purpose of this dissertation was to test the hypothesis that complement contributes significantly to myocardial reperfusion injury and drugs known as glycosaminoglycans protect the heart from reperfusion injury by inhibiting complement activation. The importance of the complement system in mediating myocardial reperfusion injury was demonstrated by studies performed in animals genetically deficient in the complement protein, C6. Myocardial damage was significantly less in C6-deficient rabbits compared to C6-competent animals. Other inflammatory mediators measured in the C6-deficient animals also were significantly lowered, suggesting an important role for complement in reperfusion injury. Likewise, the use of the glycosaminoglycan, N-acetylheparin, in an animal model of ischemic and reperfusion injury resulted in significantly reduced myocardial necrosis. The reduced myocardial necrosis correlated with a reduction in white blood cell (neutrophil) infiltration into the ischemic and reperfused heart, as well as a reduction in the inflammatory components, membrane attack complex and interleukin-8. In addition, the low-molecular-weight glycosaminoglycan, reviparin-sodium, protected the human plasma-perfused rabbit isolated heart from complement-mediated injury. Myocardial dysfunction occurred in vehicle-treated hearts, whereas myocardial function was preserved in reviparin-treated hearts. Immunohistochemistry for the complement protein complex, membrane attack complex, demonstrated an inhibition of the complement system, suggesting that reviparin-sodium protected the isolated rabbit heart by inhibiting activation of the complement system. The results in this dissertation support the hypothesis that complement contributes significantly to myocardial injury, and glycosaminoglycans protect the heart from damage mediated by complement activation. The results of these studies provide new information that may aid in the development of more effective anti-inflammatory glycosaminoglycans, which can be used in any pathophysiological condition involving inflammation.PhDHealth and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/130793/2/9811155.pd