title: Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (B.S., B.K., R.R.N.); and Department of Pharmacology (S.P.) and Department of Internal Medicine (K.B.A.), University of Michigan, Ann Arbor, Michigan sjogren1@msu.edu.
authors.forename: Benita
authors.initials: B
authors.lastname: Sjögren
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (B.S., B.K., R.R.N.); and Department of Pharmacology (S.P.) and Department of Internal Medicine (K.B.A.), University of Michigan, Ann Arbor, Michigan.
authors.forename: Sergio
authors.initials: S
authors.lastname: Parra
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (B.S., B.K., R.R.N.); and Department of Pharmacology (S.P.) and Department of Internal Medicine (K.B.A.), University of Michigan, Ann Arbor, Michigan.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Atkins
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (B.S., B.K., R.R.N.); and Department of Pharmacology (S.P.) and Department of Internal Medicine (K.B.A.), University of Michigan, Ann Arbor, Michigan.
authors.forename: Behirda
authors.initials: B
authors.lastname: Karaj
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (B.S., B.K., R.R.N.); and Department of Pharmacology (S.P.) and Department of Internal Medicine (K.B.A.), University of Michigan, Ann Arbor, Michigan.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004077:Digoxin / Q000494:pharmacology*; D006331:Heart Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D020710:RGS Proteins / Q000096:biosynthesis* / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; C105345:Rgs2 protein, mouse; D004077:Digoxin; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase