Loss of Secreted Frizzled-Related Protein-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in Human Cardiomyopathy

Abstract

Background The Wnt/β-catenin signaling pathway plays a central role during cardiac development and has been implicated in cardiac remodeling and aging. However, the role of Wnt modulators in this process is unknown. In the present study, we examined the role of the Wnt signaling inhibitor sFRP-1 in aged wildtype and sFRP-1 deficient mice. Methods and Results sFRP-1 gene deletion mice were grossly normal with no difference in mortality but developed abnormal cardiac structure and dysfunction with progressive age. Ventricular dilation and hypertrophy in addition to deterioration of cardiac function and massive cardiac fibrosis, all features present in dilated cardiomyopathy was observed in the aged sFRP-1 KO mice when aged. Loss of sFRP-1 led to increased expression of Wnt ligands (Wnt1, 3, 7b, 16) and Wnt target genes (Wisp1, Lef1) in aged hearts, which correlated with increased protein levels of β-Catenin. Cardiac fibroblasts lacking endogenous sFRP-1 showed increased αSMA expression, higher cell proliferation rates and increased collagen production consistent with the cardiac phenotype exhibited in aged sFRP-1 KO mice. The clinical relevance of these findings was supported by the demonstration of decreased sFRP-1 gene expression and increased Wisp-1 levels in the left ventricles of patients with ischemic dilated cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Conclusions This study identifies a novel role for sFRP-1 in age-related cardiac deterioration and fibrosis. Further exploration of this pathway will identify downstream molecules important in these processes and also suggest the potential use of Wnt signaling agents as therapeutic targets for age-related cardiovascular disorders in humans.

A MicroRNA Derived From Schistosoma japonicum Promotes Schistosomiasis Hepatic Fibrosis by Targeting Host Secreted Frizzled-Related Protein 1

“…To investigate involvement of the Wnt/β-catenin signaling in the sja-miR-1-mediated activation of HSCs, the protein level of β-catenin was detected in HSCs treated with sja-miR-1 mimics or Sfrp1 siRNA. Consistent with previous reports that SFRP1 functioned as a negative modulator of Wnt/β-catenin pathway (Sklepkiewicz et al, 2015), western blot analysis showed that the nuclear protein level of β-catenin was increased in the HSCs transfected with sja-miR-1 mimics or Sfrp1siRNA compared with the controls, whereas no significant difference was detected in the cytoplasm protein level of β-catenin (Figure 5C). Next, we analyzed β-catenin level in primary HSCs isolated from mice treated with the sponge vector and showed that β-catenin protein was obviously decreased in total HSCs homogenate and the nuclear protein compared with the control vector (Figure 5D).…”

“…SFRP1 protein functions as a negative regulator of Wnt/β-catenin signaling via inhibiting the binding of the Wnt receptor and thereby suppressing ligand-receptor interactions and signal transduction (Jones and Jomary, 2002;Kang et al, 2014). The reduction in production of SFRP1 leads to the activation of Wnt/β-catenin signaling pathways (Sklepkiewicz et al, 2015). It was demonstrated that the expression of fibrosis-related markers was elevated in SFRP1 knock-out mice (Matsuyama et al, 2014;Sklepkiewicz et al, 2015).…”

“…The reduction in production of SFRP1 leads to the activation of Wnt/β-catenin signaling pathways (Sklepkiewicz et al, 2015). It was demonstrated that the expression of fibrosis-related markers was elevated in SFRP1 knock-out mice (Matsuyama et al, 2014;Sklepkiewicz et al, 2015). Here, our study revealed that Sfrp1 gene was a direct target gene of sja-miR-1 both in vitro and in vivo models, and the sja-miR-1 mediated down-regulation of Sfrp1 elevated the expression of collagens and α-SMA and thereby activated the HSCs.…”

Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling

“…Cumulative evidence links pathological VH to the increased expression of β-catenin [12,40]. A study by Zheng et al [26] implicated β-catenin in the pathophysiology of hypertension, which is the main risk factor of LVH in clinical settings [2].…”

Wnt-β Catenin Signaling Pathway: A Major Player in the Injury Induced Fibrosis and Dysfunction of the External Anal Sphincter

“…However, based on several current reports, it is clear that the sFRPs act as a Wnt-decoy receptor due to their structural resemblance to Wnt frizzled receptor to inhibit β-catenin signaling 26–29 . (2) Our data only suggests but does not entirely prove that the Wnt-β catenin is necessary for the EAS injury-related fibrosis, which would require additional in-vivo and in vitro experiments and that is the goal of our future studies.…”