Regulator of
G protein signaling (
RGS) proteins have emerged as novel drug targets since their discovery almost two decades ago. RGS2 has received particular interest in cardiovascular research due to its role in regulating Gqsignaling in the heart and vascular smooth muscle. RGS2(-/-)mice are hypertensive, prone to
heart failure, and display accelerated kidney
fibrosis. RGS2 is rapidly degraded through the
proteasome, and human mutations leading to accelerated RGS2 protein degradation correlate with
hypertension. Hence, stabilizing RGS2
protein expression could be a novel route in treating
cardiovascular disease. We previously identified
cardiotonic steroids, including
digoxin, as selective stabilizers of RGS2
protein in vitro. In the current study we investigated the functional effects of
digoxin-mediated RGS2
protein stabilization in vivo. Using freshly isolated myocytes from wild-type and RGS2(-/-)mice treated with vehicle or low-dose
digoxin (2µg/kg/day for 7 days) we demonstrated that agonist-induced cAMP levels and cardiomyocyte contractility was inhibited by
digoxin in wild-type but not in RGS2(-/-)mice. This inhibition was accompanied by an increase in RGS2
protein levels in cardiomyocytes as well as in whole heart tissue. Furthermore,
digoxin had protective effects in a model of cardiac injury in wild-type mice and this protection was lost in RGS2(-/-)mice.
Digoxin is the oldest known
therapy for
heart failure; however, beyond its activity at the Na(+)/K(+)-
ATPase, the exact mechanism of action is not known. The current study adds a novel mechanism, whereby through stabilizing RGS2
protein levels
digoxin could exert its protective effects in the failing heart.