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

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Loss of Secreted Frizzled-Related Protein-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in Human CardiomyopathyCLINICAL PERSPECTIVE by Piotr Sklepkiewicz, Takayuki Shiomi, Rajbir Kaur, Jie Sun, Susan Kwon, Becky Mercer, Peter Bodine, Ralph Theo Schermuly, Isaac George, P. Christian Schulze, and Jeanine M. D’Armiento Circ Heart Fail Volume 8(2):362-372 March 17, 2015 Copyright © American Heart Association, Inc. All rights reserved.

Expression of secreted frizzled-related protein-1 (sFRP-1) in the normal heart during aging. Expression of secreted frizzled-related protein-1 (sFRP-1) in the normal heart during aging. A, Immunohistochemical staining of sFRP-1 in heart sections of sFRP-1 wild-type (WT) mice aged 3 months (a and b) with IgG controls (c and d). Sections were counterstained with hematoxylin. Magnification is ×40. Scale bars represent length of 100 μm. B, mRNA expression of sFRP-1 in the hearts of sFRP-1 WT mice at 3, 6 (n=3), and 12 months (n=4) analyzed by real-time polymerase chain reaction with β-actin used as a housekeeping gene control. Data are presented as fold of regulation and statistically significant differences are denoted by *P<0.05. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Age-dependent increase in cardiac size in secreted frizzled-related protein-1 (sFRP-1) knockout (KO) mice. Age-dependent increase in cardiac size in secreted frizzled-related protein-1 (sFRP-1) knockout (KO) mice. A, Representative picture from whole heart of wild-type (WT) and sFRP-1 KO mice at 12 months showing increase in heart size. B, Heart weight/body weight ratio (HW/BW; mg/g) of the sFRP-1 KO mice at 6 months and 12 months (n=5) compared with their WT littermates. Significant differences were denoted by *P<0.05 or ***P<0.001 vs control littermate hearts. All values were expressed as mean±SEM. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Development of cardiac remodeling in aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) mice. Development of cardiac remodeling in aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) mice. A, Representative hematoxylin and eosin staining of the sFRP-1 wild-type (WT) and sFRP-1 KO hearts at 1 year. Scale bars represent the length of 2 mm. B–D, Echocardiographic analysis of the sFRP-1 WT and KO mice hearts representing (WT/n=3; KO/n=7): (B) left ventricular end-diastolic dimension (LVEDD, cm), (C) LV posterior wall thickness (PW, cm), and (D) fractional shortening (FS, %). Significant differences were denoted by *P<0.05 or **P<0.01 vs control littermate hearts. All values were expressed as mean±SEM. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Deterioration of left ventricular (LV) function in aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) mice. Deterioration of left ventricular (LV) function in aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) mice. Hemodynamic analysis of LV systolic (A and B) and diastolic (C and D) function in sFRP-1 KO mice compared with their WT littermates at 6 and 12 months (WT/n=4; KO/n=6) representing: (A) LV systolic pressure (LVSP, mm Hg), (B) dP/dT max (mm Hg/s), (C) LV end-diastolic pressure (LVEDP, mm Hg), and (D) dP/dT min (mm Hg) value as below 0. Significant differences were denoted by *P<0.05 vs control littermate hearts. All values were expressed as mean±SEM. E, Immunohistochemical staining of Connexin43 in heart sections at 6 and 12 months. Sections were counterstained with hematoxylin. Magnification is ×40. Scale bars represent length of 100 μm. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Induction of Wnt signaling ligands in aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) hearts. mRNA analysis of the Wnt target genes in the hearts of sFRP-1 wild-type (WT) and KO mice. Induction of Wnt signaling ligands in aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) hearts. mRNA analysis of the Wnt target genes in the hearts of sFRP-1 wild-type (WT) and KO mice. A, Wnt target gene array analysis (Sabiosciences). Selected genes expression relevant to canonical Wnt signaling pathway in 12 months old hearts of sFRP-1 WT and KO mice (n=3) were outlined in the table. Statistical analysis was performed by Sabiosciences Web-based software automatically. B–E, Real-time polymerase chain reaction analysis confirmation of extracellular Wnt ligands, such as (B) Wnt7b, (C) Kremen1, (D) Wnt5a, and (E) Wnt16 in 6- and 12-month-old hearts of sFRP-1 WT and KO mice (n=5). β-Actin was used as a housekeeping control, data are presented as fold of regulation. Significant differences were denoted by *P<0.05, **P<0.01, or ***P<0.001 vs control littermate hearts. All values were expressed as mean±SEM. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Age-related increase in canonical Wnt signaling in secreted frizzled-related protein-1 (sFRP) knockout (KO) hearts. Age-related increase in canonical Wnt signaling in secreted frizzled-related protein-1 (sFRP) knockout (KO) hearts. A and B, Protein expression of β-catenin analyzed by Western blotting in control sFRP-1 WT hearts vs sFRP-1 KO hearts at 6 months (A) and 12 months (B). β-Actin was used as a housekeeping loading control. C, Representative immunofluorescent staining for β-catenin merged with DAPI in the myocardium of sFRP-1 KO compared with WT hearts at 6 and 12 months. Magnification is ×20. Scale bars represent length of 100 μm. D and E, mRNA analysis of β-catenin and Lef1 in sFRP-1 KO vs WT hearts at 6 and12 months of age (n=5). β-actin was used as a housekeeping control, data are presented as fold of regulation. Significant differences were denoted by *P<0.05 vs control littermate hearts. All values were expressed as mean±SEM. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Development of cardiac fibrosis in myocardium of aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) hearts. Development of cardiac fibrosis in myocardium of aged secreted frizzled-related protein-1 (sFRP-1) knockout (KO) hearts. A, Representative pictures for Masson staining in the heart myocardium of sFRP-1 KO at 6 months or 12 months old mice vs wild-type (WT) littermates. Magnification is ×40 and ×20 (inset). Scale bars length is 100 μm. B, Wisp1 mRNA expression by Taqman real-time polymerase chain reaction in 6 and 12 months old sFRP-1 KO hearts in vs WT hearts (n=5). C, Expression of collagens (1 and 3) in primary cardiac fibroblasts, isolated from sFRP-1 WT hearts (n=3). D, mRNA expression of sFRP-1 in cardiac fibroblast isolated from sFRP-1 WT and KO mice (n=3). E, Protein concentration of collagen in the media of sFRP-1 WT and KO fibroblasts measured by Sircol assay (n=5). F, Proliferation capacity of cardiac fibroblasts isolated from sFRP KO mice vs WT mice measured by [3H]-Thymidine uptake (n=6). Values are expressed in counts per minute (cpm). α-Smooth muscle actin (α-SMA) protein level in primary cardiac fibroblast isolated from sFRP-1 WT and KO mice analyzed by Western blot (G) and subsequently quantified by densitometry (H). β-actin was used as a housekeeping control, data are presented as fold of regulation. Significant differences were denoted by **P<0.01 or ***P<0.001 vs control littermate hearts. All values were expressed as mean±SEM. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.

Downregulation of secreted frizzled-related protein-1 (sFRP-1) and upregulation of Wisp-1 in human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). Downregulation of secreted frizzled-related protein-1 (sFRP-1) and upregulation of Wisp-1 in human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). A, mRNA expression analysis of sFRP-1 and Wisp-1 in the heart left ventricles of Control patients (n=7) or in DCM (n=8) and ICM patients (n=7). β-actin was used as a housekeeping control, data are presented as fold of regulation. Significant differences were denoted by **P<0.01 or ***P<0.001 vs control littermate hearts. All values were expressed as mean±SEM. Piotr Sklepkiewicz et al. Circ Heart Fail. 2015;8:362-372 Copyright © American Heart Association, Inc. All rights reserved.