Role of Caveolae in Cardiac Protection

Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality. The molecular signaling pathways involved in cardiac protection from myocardial ischemia/reperfusion injury are complex. An emerging idea in signal transduction suggests the existence of spatially organized complexes of signaling molecules in lipid-rich microdomains of the plasma membrane known as caveolae. Caveolins—proteins abundant in caveolae—provide a scaffold to organize, traffic, and regulate signaling molecules. Numerous signaling molecules involved in cardiac protection are known to exist within caveolae or interact directly with caveolins. Over the last 4 years, our laboratories have explored the hypothesis that caveolae are vitally important to cardiac protection from myocardial ischemia/reperfusion injury. We have provided evidence that (1) caveolae and the caveolin isoforms 1 and 3 are essential for cardiac protection from myocardial ischemia/reperfusion injury, (2) stimuli that produce preconditioning of cardiac myocytes, including brief periods of ischemia/reperfusion and exposure to volatile anesthetics, alter the number of membrane caveolae, and (3) cardiac myocyte-specific overexpression of caveolin-3 can produce innate cardiac protection from myocardial ischemia/reperfusion injury. The work demonstrates that caveolae and caveolins are critical elements of signaling pathways involved in cardiac protection and suggests that caveolins are unique targets for therapy in patients at risk of myocardial ischemia

Rapid maturation of effector T cells in tumors, but not lymphoid organs, during tumor regression.

Increasing the efficacy of adoptively transferred, tumor antigen specific T cells is a major goal of immunotherapy. Clearly, a more thorough understanding of the effector phase of T cell responses, within the tumor site itself, would be beneficial. To examine this issue, we adoptively transferred tumor antigen-specific effector T cells into tumor-bearing mice, then performed kinetic evaluations of their phenotype, function, and survival in tumors, draining lymph nodes (dLNs), and spleens during regression of murine fibrosarcomas. Effector function in tumors was quantitated through the use of a novel intratumoral cytolytic assay. This approach revealed dynamic changes in the phenotype, cytolytic capacity, and viability of tumor infiltrating effector T cells during the course of tumor regression. Over a period of days, T cells within tumors rapidly transitioned from a CD25(hi)/CD27(hi) to a CD25(low)/CD27(low) phenotype and displayed an increase in cytolytic capacity, indicative of effector maturation. Simultaneously, however, the viability of maturing T cells within tumors diminished. In contrast, transferred T cells trafficking through lymphoid organs were much more static, as they maintained a stable phenotype, robust cytolytic activity, and high viability. Therefore, there exists a marked phenotypic and functional divergence between tumor-infiltrating effector T cells and their counterparts in lymphoid organs. Our results indicate that the population of tumor-infiltrating T cells is unique in experiencing rapid effector maturation post-transfer, and suggest that strategies aimed at prolonging the survival of CD25(low)/CD27(low) full effectors, which displayed the highest levels of intratumoral cytolytic activity, should enhance the efficacy of T cell based tumor immunotherapies