Secreted Frizzled-Related Protein-1 Improves Postinfarction Scar Formation Through a Modulation of Inflammatory Response

Abstract

Objective-The inflammatory response after myocardial infarction plays a crucial role in the healing process. Lately, there is accumulating evidence that the Wnt/Frizzled pathway may play a distinct role in inflammation. We have shown that secreted frizzled-related protein-1 (sFRP-1) overexpression reduced postinfarction scar size, and we noticed a decrease in neutrophil infiltration in the ischemic tissue. We aimed to further elucidate the role of sFRP-1 in the postischemic inflammatory process. Methods and Results-We found that in vitro, sFRP-1 was able to block leukocyte activation and cytokine production. We transplanted bone marrow cells (BMCs) from transgenic mice overexpressing sFRP-1 into wild-type recipient mice and compared myocardial healing with that of mice transplanted with wild-type BMCs. These results were compared with those obtained in transgenic mice overexpressing sFRP-1 specifically in endothelial cells or in cardiomyocytes to better understand the spatiotemporal mechanism of the sFRP-1 effect. Our findings indicate that when overexpressed in the BMCs, but not in endothelial cells or cardiomyocytes, sFRP-1 was able to reduce neutrophil infiltration after ischemia, by switching the balance of pro-and antiinflammatory cytokine expression, leading to a reduction in scar formation and better cardiac hemodynamic parameters. Conclusion-sFRP-1 impaired the loop of cytokine amplification and decreased neutrophil activation and recruitment into the scar, without altering the neutrophil properties. These data support the notion that sFRP-1 may be a novel antiinflammatory factor protecting the heart from damage after myocardial infarction. (Arterioscler Thromb Vasc Biol. 2011;31:e80-e87.)

The Role of Inflammation in Myocardial Infarction

“…These observations were correlated to reduced rupture incidence and scar size while cardiac performance parameters were improved [308]. This study confirms that a fine balance between anti-and proinflammatory factors is crucial for the early wound-healing post-MI, however, more research is needed to investigate the effects of Wnt signaling manipulations in the early inflammatory response post-MI, before any firm conclusions can be drawn.…”

Wnt Signaling in Cardiac Disease

“…sFRP1, overexpressed in BMCs, was able to diminish leukocyte infiltration following MI, by switching the pro-and anti-inflammatory cytokine balance, resulting in a decreased scar size and better cardiac function. These effects were not observed in mice overexpressing sFRP1 in endothelial cells or cardiomyocytes, indicating a specific role for sFRP1 in the inflammatory response (16).…”

sfrp1 promotes cardiomyocyte differentiation in Xenopus via negative-feedback regulation of Wnt signalling

“…Mammalian Sfrp1 is also strongly expressed in embryonic myocardium, differentiated heart muscle and cardiomyocytes, and, as in Xenopus, expression is specifically excluded from the pericardium (Jaspard et al, 2000). Remarkably, Sfrp1 is transiently upregulated in a mouse model following experimentally induced myocardial infarction, predominantly at the infarct border zone, and, moreover, transgenic overexpression of Sfrp1 in the mouse model resulted in reduced infarct size and improved recovery (Barandon et al, 2003), which has since been found to be part of a coordinated response to myocardial infarction that also involves increased neovascularisation and reduced inflammatory response and scar formation (Barandon et al, 2011). During early mammalian heart development, Sfrp1 appears to function at least partially redundantly with other factors (Trevant et al, 2008), specifically Sfrp2, which, however, also mediates prominent Wnt-independent functions in the heart (Kobayashi et al, 2009).…”