UC San Diego

Heart failure occurs when the heart is unable to maintain sufficient blood flow to the body. In response the body retains salt and water, secretes neuro-hormones, and activates a variety of signaling cascades within the heart to increase cardiac function. However, these temporary changes ultimately add to the growing problem facing the myocardium. Unfortunately, the signaling involved in heart failure is highly complex, involving a vast variety of receptors, mediators, and end effectors. Rather than focusing on a unique isolated pathway, it may be preferable to understand the temporal and spatial organization and localization of these proteins and how this affects signaling involved in heart failure. Caveolae are small flask like invaginations of the plasma membrane. Their constituents include cholesterol, glycosphingolipids, caveolins (Cav), and numerous other proteins including signaling molecules involved in the prevention and progression of heart failure. Cav, the structural proteins that are responsible for caveolae formation have also been implicated in numerous signaling cascades involved in heart failure. I hypothesized that Cav-3 is essential for temporal and spatial organization of specific protective molecules and protects against heart failure and that modulation of Cav-3 can induce cardiac protection and inhibit hypertrophy possibly by the increased expression of atrial natriuretic peptide (ANP: a cardioprotective, anti-fibrotic, and anti-hypertrophic protein). This dissertation utilized various in vivo (Cav-3 overexpressing and knockout mice) and in vitro (adult cardiac myocytes) techniques along with molecular (Cav-3 adenovirus), biochemical, and histological analysis to understand the importance of Cav-3 in cardiac protection and cardiac hypertrophy. The results reveal that Cav-3 was not only essential to induce cardiac protection, but also that myocyte-specific overexpression of Cav-3 (Cav-3 OE) protects the heart from lethal ischemia/reperfusion (I/R) injury and pressure-induced cardiac hypertrophy. Interestingly, as Cav-3 expression increased, ANP expression also increased. These results suggest that modulating Cav-3 expression alters caveolae formation and increases ANP expression, as a mechanism that protects the myocardium from lethal I/R injury and cardiac hypertrophy.