title: Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction.
abstract: Secreted frizzled related protein 2 (Sfrp2) is known as an inhibitor for the Wnt signaling. In recent studies, Sfrp2 has been reported to inhibit the activity of Xenopus homolog of mammalian Tolloid-like 1 metalloproteinase. Bone morphogenic protein 1 (Bmp1)/Tolloid-like metalloproteinase plays a key role in the regulation of collagen biosynthesis and maturation after tissue injury. Here, we showed both endogenous Sfrp2 and Bmp1 protein expressions were up-regulated in rat heart after myocardial infarction (MI). We hypothesize that Sfrp2 could inhibit mammalian Bmp1 activity and, hence, the exogenous administration of Sfrp2 after MI would inhibit the deposition of mature collagen and improve heart function. Using recombinant proteins, we demonstrated that Sfrp2, but not Sfrp1 or Sfrp3, inhibited Bmp1 activity in vitro as measured by a fluorogenic peptide based procollagen C-proteinase activity assay. We also demonstrated that Sfrp2 at high concentration inhibited human and rat type I procollagen processing by Bmp1 in vitro. We further showed that exogenously added Sfrp2 inhibited type I procollagen maturation in primary cardiac fibroblasts. Two days after direct injection into the rat infarcted myocardium, Sfrp2 inhibited MI-induced type I collagen deposition. As early as 2 wk after injection, Sfrp2 significantly reduced left ventricular (LV) fibrosis as shown by trichrome staining. Four weeks after injection, Sfrp2 prevented the anterior wall thinning and significantly improved cardiac function as revealed by histological analysis and echocardiographic measurement. Our study demonstrates Sfrp2 at therapeutic doses can inhibit fibrosis and improve LV function at a later stage after MI.
authors.affiliation: Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Lunan
authors.initials: L
authors.lastname: Zhang
authors.forename: Aiguo
authors.initials: A
authors.lastname: Ni
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D000818:Animals; D055395:Bone Morphogenetic Protein 1 / Q000032:analysis / Q000037:antagonists & inhibitors; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy*; D051157:Frizzled Receptors / Q000008:administration & dosage / Q000032:analysis* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy; D016277:Ventricular Function, Left / Q000187:drug effects*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D055395:Bone Morphogenetic Protein 1; D024042:Collagen Type I; D051157:Frizzled Receptors; D008565:Membrane Proteins; C503650:Sfrp2 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C525708:Bmp1 protein, rat