RT Journal Article SR Electronic T1 Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 311 OP 319 DO 10.1124/jpet.115.231571 VO 357 IS 2 A1 Benita Sjögren A1 Sergio Parra A1 Kevin B. Atkins A1 Behirda Karaj A1 Richard R. Neubig YR 2016 UL http://jpet.aspetjournals.org/content/357/2/311.abstract AB 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 Gq signaling 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 (2 µg/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.