Recombinant frizzled1 protein attenuated cardiac hypertrophy after myocardial infarction via the canonical Wnt signaling pathway

Abstract

Postinfarct cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of myocardial infarction (MI). Here we hypothesized that frizzled1 (FZD1), a receptor of the canonical Wnt signaling pathway, is a novel mediator of ischemia-associated cardiac hypertrophy. MI was induced in mice by left anterior descending (LAD) coronary occlusion. One week after MI, the expression of FZD1 was found to be notably increased in the left ventricles (LVs) of the MI-mice compared to shams. Mouse recombinant FZD1 protein (RFP) was subcutaneously injected in the mice to provoke autoimmunization response. Anti-FZD1 antibody titer was significantly increased in the plasma of RFP-treated mice. RFP significantly mitigated the MI-induced cardiac hypertrophy and improved cardiac function in the MI mouse hearts. Moreover, increased heart and LV weights, myocardial size and the expression of β-myosin heavy chain in the MI-mice were also found to be attenuated by RFP. FZD1 was found to be significantly up-regulated in hypoxia-treated neonatal rat cardiomyocytes (NRCMs). Silencing FZD1 by siRNA transfection notably repressed the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, activation of canonical Wnt signaling induced by MI, e.g., β-catenin and glycogen synthase kinase-3β, was restrained in the LVs of the MI-mice treated by RFP, these inhibition on canonical Wnt signaling was further confirmed in hypoxic NRCMs transfected with FZD1 siRNA. In conclusion, immunization of RFP attenuated cardiac hypertrophy and improved cardiac function in the MI mice via blocking the canonical Wnt signaling pathway.

Effect of Interventions in WNT Signaling on Healing of Cardiac Injury: A Systematic Review

“…Injection of mice with mouse recombinant FZD-1 protein leads to an immune response against the FZD-1 receptor, attenuating the induction of FZD-1 expression in infarcted mice. Nevertheless, this approach did not confer any effect on infarct size, even though CM hypertrophy was attenuated in immunized mice [ 40 ]. Our group used a different approach in order to target the FZD receptors.…”

Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD

“…Compared with a prevalence of less than 20% in the general population, cardiac hypertrophy affects up to 70% of patients during moderate CKD and approaches 90% of patients on dialysis (40). Although elevated FGF23 is associated with cardiac hypertrophy, the extent of soft tissue calcifications (41), anemia (42), tissue hypoxia (43), inflammation (44), and paracrine/autocrine factors such as Wnt-related proteins and other FGFs (45,46), which likely play significant roles, remains to be determined. Thus, the complete functions of FGF23 in maintaining mineral homeostasis, as well as its potential crosstalk with other metabolic systems in CKD, are not fully understood.…”

Circular RNA ITCH mediates H2O2‐induced myocardial cell apoptosis by targeting miR‐17‐5p via wnt/β‐catenin signalling pathway

“…In addition correlation between miR‐17‐5p and circ‐ITCH revealed that miR‐17‐5p could restore the protective functions of circ‐ITCH in myocardial cells. According to previous studies, Wnt/β‐catenin signalling pathway could accelerate process of cardiovascular diseases 39 , 40 . In this study, we also measured proteins in the Wnt/β‐catenin signalling pathway, which revealed that Wnt3a, Wnt5a and β‐catenin levels were all upregulated.…”

“…According to previous studies, Wnt/β-catenin signalling pathway could accelerate process of cardiovascular diseases. 39,40 In this study, we also measured proteins in the Wnt/β-catenin signalling pathway, which revealed that Wnt3a, Wnt5a and β-catenin levels were all upregulated. After Wnt inhibitor, NCB-0846 was applied, levels of Wnt3a, Wnt5a and β-catenin were decreased, which upregulated viability of H9c2 cells as well as ATP concentrations and suppressed apoptosis rate and related protein expression.…”