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)/Tolloidlike 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.M yocardial infarction and postinfarction heart failure are the major cause of mortality and morbidity in the United States. Recently, stem-and progenitor-based cell therapy has shown promise in the treatment of myocardial infarction, yet the underlying mechanism remains elusive. We reported that intracardiac implantation of genetically modified mesenchymal stem cell overexpressing Akt (Akt-MSC) dramatically reduced infarct size and restored cardiac function in rodent hearts after coronary artery ligation (1). We postulated that the beneficial effects of Akt-MSC are paracrine in nature (2, 3) and identified Sfrp2 as a key factor released by Akt-MSC-mediating myocardial survival and repair (4).Sfrps are secreted proteins that structurally resemble the Wnt frizzled receptors and serve as modulators of Wnt signaling (5). Recent studies demonstrated that the Secreted Frizzled (Sizzled) protein (sfrp related protein in Xenopus and zebrafish) played an important role in dorsal-ventral patterning by stabilizing Chordin through the inhibition of the Tolloid-family metalloproteinase in Xenopus (Xolloid-related, Xlr) (6) and Zebrafish (Tolloid-like 1, Tll1) (7). Interestingly, Lee et al. (6) showed that recombinant mammalian Sfrp2 could also inhibit Chordin cleavage by inhibiting Xlr, a Xenopus homolog of mammalian Tolloid (mTLD)-like 1. The...