Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • He, W; Zhang, L; Ni, A; Zhang, Z; Mirotsou, M; Mao, L; Pratt, RE; Dzau, VJ

Published Date

  • December 7, 2010

Published In

Volume / Issue

  • 107 / 49

Start / End Page

  • 21110 - 21115

PubMed ID

  • 21078975

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1004708107

Language

  • eng

Conference Location

  • United States