Mouse strain determines the outcome of wound healing after myocardial infarction

Borne, Susanne W.M. van den; Schans, Veerle A.M. van de; Strzelecka, Agnieszka; Vervoort-Peters, H.T.M.; Lijnen, Peter; Cleutjens, Jack P.M.; Smits, J. F. M.; Daemen, Mat J.A.P.; Janssen, Ben J. A.; Blankesteijn, W. Matthijs

doi:10.1093/cvr/cvp207

Cited by 136 publications

(115 citation statements)

References 25 publications

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“…Although Clarke et al [34] recently suggested that the collagen fibre structure and the mechanical properties of infarcted tissue could vary between studies employing the same animal model, the reason behind this variation is not very well understood. Nevertheless, the discrepancy between our results and that of Fomovsky and Holmes [20] could potentially be attributed to the difference in animal strain [35,36]. It could also be due to the variation in the amount of isolated muscle fibres especially when considering the difficulty of precisely controlling the size of the infarct in the samples as we demonstrated in this study.…”

Section: Mechanical Properties Of Infarctscontrasting

confidence: 82%

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression

Sirry

Butler

Patnaik

et al. 2016

Journal of the Mechanical Behavior of Biomedical Materials

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Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression, Journal of the Mechanical Behavior of Biomedical Materials, http://dx.doi.org/10.1016Materials, http://dx.doi.org/10. /j.jmbbm.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractUnderstanding the passive mechanical properties of infarcted tissue at different healing stages is essential to explore the emerging biomaterial injection-based therapy for myocardial infarction (MI). Although rats have been widely used as animal models in such investigations, the data in literature that quantify the passive mechanical properties of rat heart infarcts is very limited. MI was induced in rats and hearts were harvested immediately (0 day), 7, 14 and 28 days after infarction onset. Left ventricle anterioapical samples were cut and underwent equibiaxial and non equibiaxial tension followed by uniaxial compression mechanical tests. Histological analysis was conducted to confirm MI and to quantify the size of the induced infarcts. Infarcts maintained anisotropy and the nonlinear biaxial and compressive mechanical behaviour throughout the healing phases with the circumferential direction being stiffer than the longitudinal direction.Mechanical coupling was observed between the two axes in all infarct groups. The 0, 7, 14 and 28 days infarcts showed 438, 693, 1048 and 1218 kPa circumferential tensile moduli. The 28 day infarct group showed a significantly higher compressive modulus compared to the other infarct groups (p= 0.0060, 0.0293, and 0.0268 for 0, 7 and 14 days groups). Collagen fibres were found to align in a preferred direction for all infarct groups supporting the observed mechanical anisotropy. The presented data are useful for developing material models for healing infarcts and for setting a baseline for future assessment of emerging mechanical-based MI therapies.

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Section: Mechanical Properties Of Infarctscontrasting

confidence: 82%

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression

Sirry

Butler

Patnaik

et al. 2016

Journal of the Mechanical Behavior of Biomedical Materials

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“…24 More recently, a similar role has been described for myofibroblasts in the infarct area, 23,[25][26][27][28] thereby preventing infarct expansion. 19,29 Moreover, myofibroblasts remain present in well-healed human infarcts for decades but are scarce in dilated infarcts obtained from heart failure patients. 30 Previously, we have shown that myofibroblasts express Fzd-1 and -2 during their migration into the infarct area.…”

Section: Discussionmentioning

confidence: 99%

“…We also tested an inactive analog of UM206 (CNKASEAMACEL) in the same dosage. MI was induced under isoflurane anesthesia, and echocardiography and hemodynamic analyses were performed as described previously 19 ; please refer to the extended methods in the online-only Data Supplement for details. All experiments were conducted according to international guidelines and approved by the Committee for Animal Research of Maastricht University.…”

Section: Animal Surgery Echocardiography and Hemodynamic Analysismentioning

confidence: 99%

Blocking of Frizzled Signaling With a Homologous Peptide Fragment of Wnt3a/Wnt5a Reduces Infarct Expansion and Prevents the Development of Heart Failure After Myocardial Infarction

et al. 2011

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Background-The molecular pathways that control the wound healing after myocardial infarction (MI) are not completely elucidated. One of these pathways is the Wnt/Frizzled pathway. In this study, we evaluated Frizzled as a novel therapeutic target for MI. These Frizzled proteins act as receptors for Wnt proteins and were previously shown to be expressed in the healing infarct. Methods and Results-Wnt/Frizzled signaling has been studied for decades, but synthetic ligands that interfere with the interaction between Wnts and Frizzled have not been described to date. Here we report the selection of 3 peptides derived from regions of high homology between Wnt3a and Wnt5a that act as antagonists for Frizzled proteins. UM206, the peptide with the highest affinity, antagonized the effect of Wnt3a and Wnt5a in different in vitro assays. Administration of UM206 to mice for 5 weeks, starting immediately after the induction of MI, reduced infarct expansion and increased the numbers of capillaries and myofibroblasts in the infarct area. Moreover, heart failure development was inhibited by this therapy. Key Words: heart failure Ⅲ myocardial infarction Ⅲ myofibroblasts Ⅲ pharmacology Ⅲ receptor blocker Ⅲ Wnt/frizzled pathway T he importance of Wnt signaling in developmental processes like cell proliferation, differentiation, and migration has been recognized for decades. 1,2 Wnt signaling has also been implicated in several diseases including cancer. 3,4 Although less well studied, there is growing evidence for a role of Wnt signaling in cardiovascular diseases, particularly in the remodeling that takes place in response to myocardial infarction (MI). [5][6][7][8] The underlying mechanism of Wnt signaling in cardiovascular diseases, however, is fundamentally different from that in, for example, colon cancer, in which mutations in the downstream signaling pathway lead to uncontrolled signaling and contribute to cell proliferation in the primary tumor. In cardiovascular diseases, no such mutations have been found to date. Instead, the increased expression of components of the Wnt signaling pathway suggests an activation rather than a disorder of the pathway. 7,8 Conclusions-Blocking Clinical Perspective on p 1635The involvement of Wnt signaling in multiple disease processes has fueled an intensive search for compounds that can modulate the activity of this pathway. 7,9 -11 The major focus of this research has been on the signal transduction pathway where ␤-catenin acts as a second messenger. The degradation of ␤-catenin is controlled by a complex containing casein kinase I, glycogen synthase kinase 3␤, axin, and adenomatous polyposis coli gene product. 4 Several wellknown compounds can attenuate Wnt signaling, including LiCl, vitamins A and D, and nonsteroidal anti-inflammatory drugs. 10 Moreover, novel drugs that inhibit glycogen synthase 1626by guest on March 28, 2012 http://circ.ahajournals.org/ Downloaded from kinase 3␤ or intervene in the interaction of ␤-catenin and T-cell factor/lymphoid enhancer factor have been descri...

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“…To quantify myofibroblast numbers in the infarct area, paraffin-embedded sections of 4 μm were stained for α-smooth muscle actin (α-SMA) as described before 19 (α-SMA monoclonal antibody; Sigma, Zwijndrecht, The Netherlands). Next, the infarcted area was planimetrically quantified for myofibroblast area in a blinded matter with vessels excluded (Qwin, Leica, Rijswijk, The Netherlands).…”

Section: Histologymentioning

confidence: 99%

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Uitterdijk

Hermans

Wijs-Meijler

et al. 2016

Laboratory Investigation

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Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (−41 ± 10%), whereas infarct mass remained stable in the Control-MI group (+3 ± 17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53 ± 0.43% vs 3.38 ± 0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling. Although left ventricular (LV) remodeling after myocardial infarction (MI) is aimed at maintaining cardiac pump function, initial infarct size, and the subsequent progressive expansion and thinning of the infarcted area constitute the main risk factors for the development of post-MI heart failure. 1 Several strategies that influence either the infarct size and/or the ensuing process of LV remodeling have been proposed as potential therapies to halt the development and progression of LV dysfunction. 2,3 Cardiac fibroblasts, which account for up to 70% of the cells present in the myocardium, regulate extracellular matrix (ECM) turnover, and have an essential role in cardiac homeostasis. Fibroblasts are more resistant to ischemia than cardiomyocytes, 4-6 and prolonged myocardial ischemia results in death of particularly the cardiomyocytes, whereas the fibroblasts survive. Fibroblasts have therefore been proposed to be a therapeutic target to influence the healing process of the infarcted myocardium. 1,5,[7][8][9] In addition to these resident fibroblasts, fibroblasts enter the infarcted tissue by migration. When present in the infarcted area, the fibroblasts gradually differentiate into their more contractile and synthetic...

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Mouse strain determines the outcome of wound healing after myocardial infarction

Abstract: The outcome of infarct healing in mice strongly depends on genetic background. On the basis of our results, we suggest that for studies on infarct rupture, the 129S6 mouse is the background of choice, whereas BalbC and Swiss mice are the preferred models to study infarct thinning post-MI.

Cited by 136 publications

References 25 publications

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression

Blocking of Frizzled Signaling With a Homologous Peptide Fragment of Wnt3a/Wnt5a Reduces Infarct Expansion and Prevents the Development of Heart Failure After Myocardial Infarction

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

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