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.