Cardiac Myocyte‐Specific Overexpression of Caveolin‐3 Enhances Physiological Response to β‐Adrenergic Receptors

Caveolins (Cavs) are scaffolding proteins essential to the formation of caveolae, membrane domains that compartmentalize numerous signaling molecules, including β‐adrenergic receptors (β‐ARs). Mice with cardiac myocyte (CM)‐specific overexpression of Cav‐3 (Cav‐3 OE) have more caveolae in CMs and are protected from ischemia‐reperfusion injury and other types of cardiac dysfunction. β 1 ARs are located throughout the plasma membrane but β 2 ­ARs preferentially localize to caveolae, where they interact with downstream signaling effectors also located in caveolae; however the mechanism by which changes in Cav‐3 expression alter β‐AR response is unknown. Cav‐3 OE, by compartmentation of interdependent signaling components of the βAR response, may change the global and isoform‐specific physiological responses to agonism. Overall βAR and adenylyl cyclase V/VI expression in Cav‐3 OE myocytes is not altered, but the distribution of βAR signaling pathway proteins to caveolae is altered. Hearts treated with the β‐AR agonist isoproterenol (Iso) showed augmented inotropy (+dP/dt) and lusitropy (‐dP/dt) in Cav‐3 OE hearts relative to TGneg. CMs isolated from Cav‐3 OE mice have increased cAMP production in response to Iso. Moreover, agonist‐promoted responsivity of β 1 ARs is not changed in these hearts. Thus, increased cardiac expression of Cav‐3 enhances Iso‐mediated positive inotropy without altering­ β 1 AR selective response. We conclude that increased expression of Cav‐3 enhances cardiac function by enhancing responsivity of the heart in a manner independent of β 1 AR. Supported by NIH HL107200 and AHA 14PRE20460372.