Myofibril damage during low-flow ischemia

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DESCRIPTION (provided by applicant): The reversible contractile dysfunction that follows episodes of low-flow ischemia is believed to represent an adaptive response to reduced coronary flow and/or transient myocardial injury. Conceptually, when flow and function are matched at some reduced level, the heart is thought to have adapted to preserve myocardial viability. If contractile function remains depressed despite the restoration of normal coronary flow, then flow and function become mismatched and the myocardium is said to be stunned. Studies in the chronically instrumented canine heart demonstrate that viable cardiac myocytes disclose areas of disrupted myofibrils when flow and function remain mismatched. Myofibril anomalies that appear following low-flow ischemia include the development of thick filament disorder within the sarcomere and myofibrillar thick filament disruption. These structural alterations are accompanied by changes in the phosphorylation of myosin binding protein-C (MyBP-C). Since MyBP-C is believed to regulate thick filament structure and function, changes in the phosphorylated state of MyBP-C may be instrumental in initiating thick filament disorder, disruption and contractile dysfunction. Other cytoskeletal elements are altered as well, including the formation of actin aggregates, disruption of intermediate filaments and depolymerization of microtubules. Small heat shock proteins, HSP27 and aB-crystallin, interact with actin and desmin, respectively, and HSC7O forms high molecular weight aggregates with tubulin. Experiments outlined in this proposal are designed to answer the following questions: (1) does dephosphorylation of MyBP-C induce contractile dysfunction; (2) does dephosphorylation of MyBP-C initiate thick filament disorder and disruption; and (3) does redistribution of small heat shock proteins and HSC7O protect myofibrillar and cytoskeletal proteins? Identifying the mechanism(s) that alter myofibril structure following low-flow ischemia may make it possible to control flow-function matching, preserve cardiocyte viability and minimize myocardial injury from repeated ischemic episodes.