Research Topic number 4: Cardiovascular and cerebrovascular aging: Behavioral, social, clinical, and biological studies of cardiovascular and cerebrovascular aging. (Established Investigator) The aged heart has increased susceptibility to ischemia but the mechanism(s) responsible for this phenomenon has not been elucidated. PKC expression has been associated with resistance to ischemia in a number of models and we have shown that overexpression of PKC in hearts of adult transgenic mice results in an increased rate of left ventricular pressure redevelopment following global ischemia when compared to control hearts. Pilot data suggest that PKC expression in the heart is reduced by aging. Therefore, the proposed experiments are designed to assess the effects of PKC expression on overall function of the senescent heart and its response to ischemia.
Three specific aims are proposed: I: To ascertain the characteristic PKC isoform profile and subcellular distribution in wild-type adult mouse heart at three time points (3, 16, and 24 months) via Western analysis. These analyses will be complemented by measurements of total in vitro PKC activity. II: To assess the ventricular hemodynamics of senescent wild type and PKC expressing hearts and their response to ischemia. Myocardial energetics will be measured by 31P NMR spectroscopy before, during and after an ischemic insult. Additionally, apoptotic indices will be obtained on these hearts and correlated to the level of protection. These results will be compared to the protective response already defined in young PKC expressing hearts. III: Determine the optimal timing of the PKC effect. It has been established that several months of expression protects the young adult heart but this may not hold in the senescent heart. An understanding of the cellular and molecular mechanisms which define the distinct cardiac responses to the physiological stress of aging may lead to novel preventative and therapeutic approaches to cardiac muscle disease in the aged.
