| Popis: |
Heart failure is a complex syndrome characterized by left ventricular dysfunction, myocardial remodeling, and biochemical alterations. Several signaling pathways are involved in the induction of pathological remodeling and heart failure; many of these pathways are linked to cardiac sarcoplasmic reticulum (SR) Ca2+ cycling, as intracellular Ca2+ handling is the central coordinator of cardiac function. Since defects in SR Ca2+ cycling are a common pathophysiological characteristic of heart failure, targeting defects in Ca2+ handling is proposed as adjunctive therapy in end-stage heart failure. Further investigating the roles of known proteins and novel proteins in the Ca2+ cycling pathway is critical in identifying the best potential targets for therapeutic drugs. A recently discovered histidine-rich calcium binding protein (HRC) may play a role in Ca2+ homeostasis in the SR. However, its specific role in SR Ca2+ cycling remains to be elucidated. Our data indicate that: (a) HRC regulates SR Ca2+ uptake and is an integral regulatory protein in the cardiac muscle Ca2+ cycling cascade; (b) an increase in HRC protein levels results in cardiac dysfunction; and (c) HRC may be a therapeutic target for heart failure. We also further investigated the role of another important Ca2+ cycling regulatory protein, phospholamban (PLN), in the context of ischemia and reperfusion. Our data reveal that decreased particulate partitioning of protein kinase C epsilon (PKCε) contributes to the increased susceptibility to ischemic injury in PLN deficient hearts and that augmentation of PKCε particulate partitioning through myocardial specific expression of a selective PKCε translocation activator, ψεRACK, in hearts at an increased risk for ischemia is sufficient to confer cardioprotection. The data generated and implications of these data suggest a promising therapeutic target for heart failure may be the recently discovered regulator of SR Ca2+ uptake, HRC, while there should be caution in targeting a well known regulator of SR Ca2+ uptake, PLN, as this may increase the risk of ischemic injury due to decreased PKCε particulate partitioning. As a result of this dissertation research, the role of HRC and PLN in the context of SR Ca2+ cycling and the progression of cardiac disease is better understood. |
