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

Abstract

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...

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

“…4 In the present study, we found that the presence of myofibroblasts, as indicated by immunohistochemistry (in which we excluded blood vessels) as well as mRNA expression (that may in part reflect α-SMA from blood vessels) for α-SMA, was higher in the infarcted tissue as compared with remote tissue and correlated not only with IM BL but also with the estimated change in IM over time in the Control-MI group, suggesting that, indeed, myofibroblasts contribute to infarct contraction. In contrast to our previous study in mice, in which UM206 treatment increased myofibroblast presence in the infarcted area, 11 myofibroblast presence was lower in the infarcted myocardium of UM206-treated swine as compared with Control-MI, particularly in swine with a large MI, despite the observation that the reduction in IM was larger. It should be noted, however, that infarct size as a percentage of the left ventricle in mice is much larger than the infarct size in swine in the present study, and therefore mechanical stress within the murine infarcts is expected to be larger.…”

“…Administration of UM206 promotes migration of fibroblasts to the infarcted area by inhibition of Wnt/Fzd signaling, and thereby modulates the scar formation in the infarcted area. 11 In accordance with our recent study in mice, 11 we found in the present study that treatment with UM206 for 5 weeks reduced infarct mass as compared with its baseline measurement. This reduction in infarct mass was accompanied by a decreased LV dilation, as measured in awake animals with echocardiography, between 3 and 5 weeks after MI in swine treated with UM206.…”

“…Targeting the Wnt signaling pathway by modulating its ligand, the Fzd receptors, through UM206, an antagonist of Fzd1 and Fzd2, has been shown to promote fibroblast migration, limit infarct size, and attenuate adverse remodeling after infarction induced by permanent ligation of the coronary artery in mice. 11,12 A potential pitfall of altering fibroblast presence is that in the remote non-infarcted myocardium, local fibroblasts may remain activated in response to volume and pressure overload and promote interstitial fibrosis. 1,13 In light of these considerations, the present study was designed to investigate whether UM206 is capable of limiting adverse LV remodeling after MI in a preclinical setting, that is, when tested in a large translational swine model of reperfused MI.…”

Heart Failure as an Aging-Related Phenotype

“…21) In other reports, blocking of Wnt/β-catenin signaling was shown to avert adverse remodeling or improve cardiac function in animal models of myocardial infarction. [22][23][24][25] In spite of such a context-dependency, Wnt/β-catenin signaling is thought to play a pivotal role in the progression of cardiac dysfunction/heart failure. 26) In the canonical Wnt/β-catenin pathway, DKK1 (Dickkopf1) basically inhibits the formation of a ternary complex consisting of LRP5/6, Frizzled, and the Wnt ligand followed by inhibition of the canonical Wnt/β-catenin pathway.…”

Transplantation of Genetic Modified Stem Cells Overexpressing Therapeutic Growth Factorsfor the Treatment of Experimental Rat Myocardial Infarction

“…Как было по казано недавно Laeremans и др. [42], пептид UM206 блокирует рецепторы, приводя к уменьшению размеров инфаркта и улучшению функционального восстановления сердца. Эти результаты доказывают, что UM206 обладает эффектом, близким к эффекту Sfrps в показате лях восстановления сердца, что далее подтвер ждает логическое обоснование того, что блоки рование рецептора (как показано в нашем ис следовании, повышением белков Sfrp) являет ся эффективным для Wnt3a и его нежелатель ного влияния на миокард.…”