Kevin C.M. Hermans

Interventions in Wnt signaling as a novel therapeutic approach to improve myocardial infarct healing

Following myocardial infarction, wound healing takes place in the infarct area where the non-viable cardiac tissue is replaced by a scar. Inadequate wound healing or insufficient maintenance of the extracellular matrix in the scar can lead to excessive dilatation of the ventricles, one of the hallmarks of congestive heart failure. Therefore, it is important to better understand the wound-healing process in the heart and to develop new therapeutic agents that target the infarct area in order to maintain an adequate cardiac function. One of these potential novel therapeutic targets is Wnt signaling. Wnt signaling plays an important role in embryonic myocardial development but in the adult heart the pathway is thought to be silent. However, there is increasing evidence that components of the Wnt pathway are re-expressed during cardiac repair, implying a regulatory role. Recently, several studies have been published where the effect of interventions in Wnt signaling on infarct healing has been studied. In this review, we will summarize the results of these studies and discuss the effects of these interventions on the different cell types that are involved in the wound healing process.

Targeting the Wnt/frizzled signaling pathway after myocardial infarction: A new tool in the therapeutic toolbox?

Wnt/frizzled signaling in the adult heart is quiescent under normal conditions; however it is reactivated after myocardial infarction (MI). Any intervention at the various levels of this pathway can modulate its signaling. Several studies have targeted Wnt/frizzled signaling after MI with the majority of them indicating that the inhibition of the pathway is beneficial since it improves infarct healing and prevents heart failure. This suggests that blocking the Wnt/frizzled signaling pathway could be a potential novel therapeutic target to prevent the adverse cardiac remodeling after MI.

The Janus face of myofibroblasts in the remodeling heart

Abstract Cardiac fibrosis is a process that is associated with multiple forms of cardiac remodeling. There is an ongoing debate whether fibrosis is good or bad for cardiac function. On the one hand, deposition of extracellular matrix is indispensable for the wound healing in the injured heart; on the other hand, interstitial fibrosis can lead to stiffening of the ventricular wall and adverse remodeling. A common denominator of cardiac fibrosis is the appearance of myofibroblasts that possess smooth muscle-like contractile properties and can synthesize extracellular matrix. Traditionally, these cells were considered to merely derive from resident fibroblasts in the ventricular wall. However, recent insights suggest that myofibroblasts can originate from cell types as diverse as epicardial cells, resident mesenchymal stem cells and circulating fibrocytes. In this review, we will describe the origin(s) of the myofibroblasts in different forms of cardiac remodeling. We will also address the question whether specific mediators that are involved in the transdifferentiation of these myofibroblasts from their precursors can be identified. This would be of relevance in order to design specific interventions that would attenuate the adverse fibrotic deposition whilst preserving the favorable aspects of the fibrotic response.

Wnt signaling in atherosclerosis

Atherosclerosis is a disease of the vascular wall that forms the basis for a large spectrum of pathologies of various organs and tissues. Although massive research efforts in the last decades have yielded valuable information about its underlying molecular mechanisms, this has not led to a translation into effective therapeutic interventions that can stop the progression or even can induce regression of atherosclerosis. This underscores the importance of investigations on the involvement of novel signaling pathways in the development and progression of this condition. In this review we focus on the role of Wnt signaling in atherosclerosis. Experimental evidence is presented that Wnt signaling is involved in many aspects of the development and progression of vascular lesions including endothelial dysfunction, macrophage activation and the proliferation and migration of vascular smooth muscle cells. Subsequently, we will discuss the role of Wnt signaling in myocardial infarction and stroke, two common pathologies resulting from the progression of atherosclerotic lesions towards an unstable phenotype. Despite the fact that the published data sometimes are ambiguous or even conflicting, a picture is emerging that an attenuation of Wnt signaling is beneficial for the cardiovascular system that is compromised by atherosclerosis.

Cardiac (myo)fibroblast: Novel Strategies for its Targeting Following Myocardial Infarction

Following myocardial infarction (MI), a dynamic and complex process called wound healing is initiated, aiming to produce a robust scar and limit adverse remodeling of the left ventricle (LV). Cardiac fibroblasts (CFs) - the most populous cardiac cell-type - differentiate into myofibroblasts under the influence of post-MI mechanical stress, transforming growth factor β (TGF-β) and various inflammatory signals. Myofibroblasts are contractile cells that start producing extracellular matrix (ECM) components and secrete factors that orchestrate wound healing, but also promote adverse cardiac remodeling that can progress to life-threatening heart failure (HF). Due to their vital role in the wound healing and LV remodeling after MI, (myo)fibroblasts have been receiving more and more attention lately as targets for anti-HF treatment strategies. In this review, we will summarize the current knowledge regarding the cardiac (myo)fibroblast characteristics, discuss the signaling pathways and the factors that affect their migration, proliferation and differentiation post-MI, as well as their ECM-depositing capabilities. Finally, we will provide an overview of the latest innovative research that is targeting the (myo)fibroblast, in an attempt to limit adverse remodeling and prevent HF.

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

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.

WNT Signaling in Cardiac and Vascular Disease

WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-β and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.

Wnt Signaling in Cardiac Remodeling and Heart Failure

Wnt signaling plays an essential role during development, but is also activated in diseases as diverse as neurodegeneration, osteoporosis, and cancer. Accumulating evidence demonstrates that Wnt signaling is also activated during cardiac remodeling and heart failure. In this chapter, we will provide a brief overview of Wnt signaling in all its complexity. Then we will discuss the evidence for its involvement in the development of cardiac hypertrophy, the wound healing after myocardial infarction (MI) and heart failure. Finally, we will provide an overview of the drugs that are available to target Wnt signaling at different levels of the signaling cascade and the results of these pharmacological interventions in cardiac disease.

Mimicking the Binding Sites of Wnt Proteins: Rational Design of Wnt/Fzd-Signaling Modulators

The interaction between Wnt proteins and Frizzled (Fzd) receptors is a key event that activates all the Wnt signaling pathways [1]. Aberrant regulation of Wnt signaling is linked to a variety of diseases, and compounds that interfere with Wnt/Fzd interactions are potentially useful for their diagnosis and therapeutics. The aim of the present work was to develop peptides that bind to Fzds, and are able to modulate Wnt/Fzd-signaling. In order to develop such compounds, we sought to mimic the Fzd-binding sites of Wnt proteins. Although there is limited structural information on the features of Wnt/Fzd interactions, it is likely that all Wnt proteins interact with Fzds through their β2and β3-loop regions [2]. These regions are highly conserved among the different Wnts, and their secondary structure is stabilized by a characteristic pattern of intraloop SS-bonds. Herein we report the design, synthesis and biological evaluation of a library of peptide mimics for the β2and β3-loop regions of Wnt3a and Wnt5a.

The role of inflammation in myocardial infarction

Coronary heart disease (CHD) is a major contributor of mortality and morbidity in the modern world and frequently develops into myocardial infarction (MI). The ischemic injury that characterizes MI is followed by an orchestrated, but highly heterogeneous, chain of events, in which the inflammatory response plays a pivotal role. The activation of the immune response is essential for the normal wound healing, a process that aims to replace the injured myocardial tissue following injury. Multiple cellular and molecular signals contribute vital functions throughout this process, the spatial and temporal aspects of which are tightly regulated. Inadequate or exaggerated response to inflammation can lead to adverse remodeling with devastating effects for the injured heart. Given the exceptional pathophysiologic complexity of the systems regulating the inflammatory response during atherogenesis and during the early wound healing following MI, several factors need to be considered in the quest for the optimal treatment. Furthermore, the currently available therapeutic arsenal targets—directly and indirectly—the inflammatory response; however, it is far from being regarded as adequate. Novel pharmacotherapeutic strategies are urgently needed in order to drastically reduce the burden of CHD. This chapter discusses the general concepts of atherosclerosis, which eventually lead to MI, and of the post-MI wound-healing process with special focus on the inflammatory components (cellular and molecular) that play decisive roles in the immune response as well as the current and innovative therapies in the field.