The applicant hopes to establish an investigative program that links the dissection of molecular pathways of cardiomyocyte growth and survival with the development of surgical interventions for heart disease. The rich collaborative environment at UCSF and the support for active involvement in both cardiothoracic surgery and molecular research are expected to foster this goal. The current proposal would help form a basis for such a long term program by demonstrating the feasibility of analyzing cardiomyocyte signaling in the context of an experimental procedure for ischemic heart failure. Early generations of surgical interventions for heart failure, based on left ventricular (LV) geometry, have failed to account for complexities of myocardial biology, including apoptotic loss of cardiomyocytes and progressive thinning and fibrosis of the peri-infarct zone. Sphingosine-1-phosphate (S1P) has been associated both with cellular hypertrophy and with protection from apoptosis in cardiac myocytes. It is therefore hypothesized that a drop in S1P signaling accompanies infarct extension and cardiomyopathy after chronic LV infarction. It is further postulated that therapeutic cardiac remodeling (TCP) achieved via ventricular scar resection is associated with an increase in S1P signaling that leads to a reduction in cardiomyocyte apoptosis and an adaptive hypertrophic response in the remaining myocardium. To test these hypotheses, a mouse model of chronic coronary ligation will be used to analyze S1P receptor 1 (S1Pi) expression and responsiveness, as well as the activity and expression of sphingosine kinase 1 (SphK1), an enzyme that regulates the balance between pro-apoptotic ceramide and anti-apoptotic S1P. This activity will be correlated to cardiomyocyte apoptosis and to changes in LV structure and function. S1P signaling will then be studied in the context of ventricular scar resection, and correlated to changes in ventricular wall structure and function. Finally, pharmacologic stimulation of SphK1 and gene transfer of S1 P! And of SphK1 will test the feasibility of an intra-operative, molecular enhancement of surgical TCR.
