Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression

Objective: Overload-induced heart failure is associated with myocyte apopto sis induced by unknown mechanisms. Wnt genes encode secreted signaling mole cules that bind to frizzled receptors and stabilize cytosolic beta-catenin which is translocated into the nucleus, acts as transcriptional activator a nd imparts an apoptosis resistant phenotype. This signaling pathway is anta gonized by secreted frizzled related proteins (sFRPs) which modulate apopto sis susceptibility in cell culture models. On the basis of these considerat ions, the present investigation compares myocardial mRNA expression of sFRP s and the level of soluble beta-catenin in tissue samples from nonfailing a nd failing hearts. Methods: Nonischemic transmural samples from human faili ng left ventricles and from nonfailing donor ventricles were used in the pr esent study. The mRNA concentration of the Wnt-antagonists sFRP 1-4 were de termined by quantitative reverse transcription polymerase chain reaction (R T-PCR). The myocardial localization of sFRP 3 and 4 expression was investig ated using in situ RT-PCR. The pool of soluble beta-catenin was quantified by Western blot analysis of protein extracts. Results: The mRNA levels of p roapoptotic sFRPs 3 and 4 but not of sFRP 1 and 2 were elevated in failing ventricles compared to donor hearts. There was no significant difference be tween patients suffering from a dilated cardiomyopathy or a coronary heart disease, sFRPs 3 and 4 were expressed in cardiomyocytes and their expressio n correlated with the mRNA expression of the proapoptotic Fas/Fas-antagonis t ratio, but inversely with the mRNA levels of the antiapoptotic bcl-x(L). The size of the pool of 0.1% Triton soluble beta-catenin tended to decrease in myocardial samples with high sFRP 3 and 4 expression levels. Conclusion s: The results support the hypothesis that in failing human myocardium the Wnt/beta-catenin pathway is attenuated by enhanced expression of two endoge nous Wnt-antagonists. This might contribute to an apoptosis susceptible phe notype of overloaded human myocardium. (C) 2000 Elsevier Science B.V. All r ights reserved.