Wnt Signaling Inhibitors as Therapeutic Approach in Ischemic Heart Disease

Abstract

Wnt (wingless-type MMTV integration site family) signaling is an evolutionary conserved system highly active during embryogenesis, but in adult hearts has low activities under normal conditions. It is essential for a variety of physiological processes including stem cell regeneration, proliferation, migration, cell polarity, and morphogenesis, thereby ensuring homeostasis and regeneration of cardiac tissue. Its dysregulation and excessive activation during pathological conditions leads to morphological and functional changes in the heart resulting in impaired myocardial regeneration under pathological conditions such as myocardial infarction, heart failure, and coronary artery disease. Several groups of Wnt inhibitors have demonstrated the ability to modulate the Wnt pathway and thereby significantly reduce fibrosis and improve cardiac function after myocardial ischemia. Their inhibitory effect can be realized at multiple levels, which include the inhibition of Wnt ligands, the inhibition of Frizzled receptors, the stabilization of the β-catenin destruction complex, and the disruption of nuclear β-catenin interactions. In this review, we overview the function of Wnt signaling in responses of cardiac cells to pathological conditions, especially ischemic heart disease, with an emphasis on the use of inhibitors of this signaling as a therapeutic approach. Finally, we summarize the current knowledge about the potential of the targeting of Wnt signaling in therapeutic applications.

Keywords: Wnt inhibitors; Wnt signaling; fibrosis; myocardial ischemia; pathological remodeling; β-catenin.

Figure 1

Wnt signaling pathways and the targets of their inhibitors. Abbreviations: Wnt—Wnt protein; Sfrp—secreted Frizzled-related protein; Dkk—Dickkopf family of secreted proteins; Wif—Wnt inhibitory factor; ROR2—receptor tyrosine kinase-like orphan receptor 2; PORCN—porcupine; Dvl—Disheveled; Rac—Rac protein kinase; JNK—c-Jun N-terminal kinase; Jun—Jun Proto-Oncogene; AP-1 —Transcription Factor Subunit; Daam1—Disheveled-associated activator of morphogenesis 1; RhoA—Ras homolog family member A; ROCK2—Rho-associated coiled-coil–containing protein kinase 2; PLC—phospholipase C; PIP2—phosphatidylinositol 4,5-bisphosphate; DAG—1,2-diacylglycerol; IP3—inositol 1,4,5-triphosphate; PKC—protein kinase-C; CAMKII—calmodulin-dependent protein kinase II; NFAT—nuclear factor of activated T cells; TNKS—tankyrase; Ck1—casein kinase 1; APC—adenomatous polyposis coli protein; GSK3 β—glycogen synthase kinase 3β; CBP—CREB binding protein; TCF/LEF—TCF/LEF transcription factors. Yellow color represents components of Planar cell polarity pathway, red color represents components of Ca²⁺-dependent Wnt signaling, blue color represents components of canonical Wnt signaling pathway, and gray arrows represent inhibitors of Wnt signaling and their site of action. More details are provided in the text.

Figure 2

The role of the Wnt signaling pathway in the development of cardiac fibrosis and potential targets of their inhibitors. Abbreviations: Wnt—Wnt protein; Ang-II—angiotensin II; TGF-ß—transforming growth factor ß; Smad—Smad proteins; JNK—c-Jun N-terminal kinase; CBP—CREB-binding protein; MMPs—matrix metalloproteinases; TIMPs— tissue inhibitors of matrix metalloproteinases; Cx43—connexin 43. Red Xs represent sites for potential inhibition of Wnt signaling. More details are provided in the text.