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.

Myofibroblasts are differentiated fibroblasts that hold a key role in wound healing and remodeling following myocardial infarction (MI). A large repertoire of stimuli, such as mechanical stretch, growth factors, cytokines, and vasoactive peptides, induces myofibroblast differentiation. Myofibroblasts are responsible for the production and deposition of collagen, leading to the establishment of a dense extracellular matrix that strengthens the infarcted tissue and minimizes dilatation of the infarct area. In addition, cells contributing to fibrosis act on sites distal from the infarct area and promote collagen deposition in noninfarcted tissue, thus contributing to adverse remodeling and consequently to the development of congestive heart failure (CHF). Current drugs that are used to treat post-MI CHF do influence fibroblasts and myofibroblasts; however, their therapeutic efficacy is far from being regarded as ideal. Novel therapeutic agents targeting (myo)fibroblasts are being developed to successfully prevent the cardiac remodeling of sites remote from the infarct area and therefore hinder the establishment of CHF. The purpose of this review article is to discuss the basic concepts of the myofibroblasts' actions in cardiac wound healing processes, factors that influence them, currently available pharmacological agents, and future challenges in this area.

Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-γ (MIG) and interferon-γ inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands (MIG, IP10, Interferon-inducible T-cell alpha chemo-attractant [I–TAC]) in patients with hypertension (≥140/90 mm Hg) associated with subclinical (n = 19) or symptomatic (n = 16) diastolic LV dysfunction on echocardiography and healthy controls. NT–pro BNP, MIG, IP10, I–TAC all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I–TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden’s index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p ≤ 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT–pro BNP, the CXCR3 ligands retained significance (p ≤ 0.028). Adding optimized thresholds for the CXCR3 ligands to NT–pro BNP enhanced (p ≤ 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I–TAC add diagnostic accuracy over and beyond NT–pro BNP.

Recent clinical studies suggest that inflammatory mediators have huge potential in individualized therapy and in efficacy screening and can be utilized as biomarkers for a plethora of pathological conditions. The standard approach for detecting and measuring these inflammatory mediators is via blood samples. Nevertheless, there is no scientific report providing solid evidence on the most suitable blood compartment that will give the optimal inflammatory mediator measurement, or regarding the diurnal variation of circulating mediators. In this study, we present the biological variability of circulating cytokines and chemokines from healthy individuals (mean age 59 years) assessed by a novel membrane-based assay. Fifteen males and an equal number of females (all above 50 years) with no known inflammatory condition were selected. Through a planar method, named Proteome Profiler™, improved with fluorescence readout into a semi-quantitative multiplex assay, a screening of 36 inflammatory mediators was performed in serum and plasma of morning and afternoon blood withdrawals. The multiplex analysis revealed that the physiological variability of several circulating inflammatory mediators was relatively small within a cohort of 30 healthy aging subjects. There was no substantial gender effect in the inflammatory mediator profile. On the contrary, most of the cytokine/chemokine values measured in the afternoon collection were found to be higher compared to the morning ones, particularly in plasma. In this study we provide evidence that circulating cytokine and chemokine levels of healthy individuals are elevated when blood is sampled in the afternoon compared to the morning, as influenced by the circulating cortisol levels. Furthermore, we report significant differences between cytokine/chemokine levels measured in serum and plasma. Our results provide essential information for future studies that will focus on examining circulating inflammatory mediator differences between healthy and diseased individuals.