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Calcium activated neutral protease : defining a physiological role in the development of cardiac hypertrophy Arthur, Gavin Donald

Abstract

Calcium activated neutral protease, calpain, is thought to be activated where intracellular calcium levels are increased. Calpain substrates include myofibrillar, cytoskeletal, ion handling and cell signalling proteins, all of which are altered during cardiac hypertrophy. No assessment of calpain during hypertrophy has been undertaken, therefore my goal was to characterise any possible role and mechanism of calpain with physiological and pathological hypertrophy in Wistar rats. Calpain's involvement in intracellular alterations during hypertrophy was assessed using the calpain inhibitor E64c. Swim exercise and injection of the P-adrenergic agonist isoproterenol were predicted to increase calpain activity. Both models induced hypertrophy with E64c able to reduce the isoproterenol induced hypertrophy. Swim exercise decreased calpain activity, while isoproterenol injection increased activity of both calpain iso forms. E64c prevented isoproterenol induced calpain increases while increasing the activity of calpastatin, calpains endogenous inhibitor. A comparison of calpain's response to swim or run exercise was carried out as these models both produce cardiac alterations. Running increased particulate fraction calpain activity of skeletal muscle and in both the soluble and particulate fractions in cardiac muscle. Swim exercise decreased cardiac and skeletal muscle calpain activities, demonstrating that striated muscle calpain responds differently to these exercise stimuli. Calpain does not seem to mediate the cardiac adaptations to swim exercise. Isoproterenol induces increased calpain activity and E64c's ability to inhibit this increase and to reduce its hypertrophy effects led me to focus on this model. Increased contractile function was demonstrated 72 hours after isoproterenol injection but not in E64c treated hearts, suggesting that underlying causes may be dependent upon calpain. Therefore, aspects of both Ca2 + homeostasis and myofibrilar composition were examined. Ca2 + uptake by the SR was significantly elevated 72 hours following isoproterenol with E64c actually increasing this effect. Certain key myofibrilar proteins were mobilized to a more cytosolic associated distribution following isoproterenol with E64c reducing this effect. Increased calpain activity may play a significant role in the development of isoproterenol induced hypertrophy. Further study of these calpain mediated processes in cardiac hypertrophy could facilitate the development of treatments to reduce the deleterious adaptations that lead to heart failure.

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