title: Effects of cardiotonic steroids on dermal collagen synthesis and wound healing.
abstract: We previously reported that cardiotonic steroids stimulate collagen synthesis by cardiac fibroblasts in a process that involves signaling through the Na-K-ATPase pathway (Elkareh et al. Hypertension 49: 215-224, 2007). In this study, we examined the effect of cardiotonic steroids on dermal fibroblasts collagen synthesis and on wound healing. Increased collagen expression by human dermal fibroblasts was noted in response to the cardiotonic steroid marinobufagenin in a dose- and time-dependent fashion. An eightfold increase in collagen synthesis was noted when cells were exposed to 10 nM marinobufagenin for 24 h (P < 0.01). Similar increases in proline incorporation were seen following treatment with digoxin, ouabain, and marinobufagenin (10 nM x 24 h, all results P < 0.01 vs. control). The coadministration of the Src inhibitor PP2 or N-acetylcysteine completely prevented collagen stimulation by marinobufagenin. Next, we examined the effect of digoxin, ouabain, and marinobufagenin on the rate of wound closure in an in vitro model where human dermal fibroblasts cultures were wounded with a pipette tip and monitored by digital microscopy. Finally, we administered digoxin in an in vivo wound healing model. Olive oil was chosen as the digoxin carrier because of a favorable partition coefficient observed for labeled digoxin with saline. This application significantly accelerated in vivo wound healing in rats wounded with an 8-mm biopsy cut. Increased collagen accumulation was noted 9 days after wounding (both P < 0.01). The data suggest that cardiotonic steroids induce increases in collagen synthesis by dermal fibroblasts, as could potentially be exploited to accelerate wound healing.
authors.affiliation: Department of Medicine, University of Toledo College of Medicine, 3000 Arlington Ave., Mail Stop 1186, Toledo, OH 43614-2598, USA.
authors.forename: Nasser
authors.initials: N
authors.lastname: El-Okdi
authors.forename: Sleiman
authors.initials: S
authors.lastname: Smaili
authors.forename: Vanamala
authors.initials: V
authors.lastname: Raju
authors.forename: Amjad
authors.initials: A
authors.lastname: Shidyak
authors.forename: Shalini
authors.initials: S
authors.lastname: Gupta
authors.forename: Larisa
authors.initials: L
authors.lastname: Fedorova
authors.forename: Jihad
authors.initials: J
authors.lastname: Elkareh
authors.forename: Sankaridrug
authors.initials: S
authors.lastname: Periyasamy
authors.forename: Anna P
authors.initials: AP
authors.lastname: Shapiro
authors.forename: M Bashar
authors.initials: MB
authors.lastname: Kahaleh
authors.forename: Deepak
authors.initials: D
authors.lastname: Malhotra
authors.forename: Zijian
authors.initials: Z
authors.lastname: Xie
authors.forename: Khew Voon
authors.initials: KV
authors.lastname: Chin
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D002018:Bufanolides / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis*; D004077:Digoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010042:Ouabain / Q000494:pharmacology; D011392:Proline / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D002018:Bufanolides; D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; C093896:marinobufagenin; D010042:Ouabain; D004077:Digoxin; D003094:Collagen; D011392:Proline; D019061:src-Family Kinases