| Popis: |
Heart failure is a leading cause of human morbidity and mortality and has been linked to neurohormonal dysregulation of β-adrenergic receptor (βAR) expression and responsivity that occurs with advancing age. No overarching mechanism for this age-dependent loss in βAR response has been identified. However, βARs localize to caveolae, membrane lipid raft microdomains formed by caveolin (Cav) proteins and expression of caveolin-3 (Cav3), the main Cav in caveolae of cardiac myocytes (CMs) decreases in an age-dependent manner. Therefore, aging-related reduction of Cav3 and caveolae may influence the loss of βAR response, and increased Cav3 expression may alter the βAR responsivity of CMs and preserve βAR function into old age.The studies presented in this dissertation were designed to understand the influence of Cav3 on the βAR signaling pathway. In chapter 1, we reviewed current knowledge of the biogenesis and degradation of Cavs and caveolae, described their composition and roles in compartmentalization of lipid and protein factors of cellular physiology, and identified unanswered questions informed by the state-of-the-art and human disease. In chapter 2, we tested the hypothesis that CM-specific Cav3 overexpression (Cav3 OE) would modify βAR responsivity in young and aged hearts. We measured the physiological sequelae of activation of βARs in young and aged hearts with the synthetic catecholamine isoproterenol (Iso). We found significant amplification of Iso dose-induced increases in physiological contractility and relaxation of young Cav3 OE hearts, which also exhibited increased responses into old age.In chapter 3, we tested the hypothesis that Cav3 OE increases caveolar compartmentation of βARs and/or downstream effectors of the βAR response and that the enhanced Cav3 OE response to Iso is mediated by β1ARs or β2ARs. Cav3 OE hearts did not demonstrate enhancement in targeted adenylyl cyclase- or βAR isoform-specific responses. However, we discovered that βAR-dependent cAMP production with Iso is subject to increased regulation by phosphodiesterase activity in Cav3 OE CMs, implicating Cav3 in differential regulation of βAR signals without significant changes in protein distribution. Our findings from the studies in this dissertation support the hypothesis that Cav3 OE amplifies βAR function in young hearts and preserves responsivity in aged animals. These results are the first to demonstrate that Cav3 OE is protective against loss of βAR responsivity in aging hearts. |
