Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure

Abstract

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/β-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/β-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/β-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.

Deficiency of heme oxygenase 1a causes detrimental effects on cardiac function

“…Pooled zebrafish larvae were lysed in chilled RIPA buffer supplemented with phosphatase and protease inhibitors (Roche) using a sonicator (Sonopuls HD2070, Bandelin, Berlin, Germany). Western blotting was performed as previously described 35 . The antibodies used are listed in Table S2.…”

“…Western blotting was performed as previously described. 35 The antibodies used are listed in Table S2 .…”

“…RNA extraction was performed with the miRNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Quantitative RT‐PCR was performed as described 35 at least three times with three technical replicates for each sample. The primer pairs used are listed in Table S1 .…”

“…Quantitative RT-PCR was performed as described 35 at least three times with three technical replicates for each sample. The primer pairs used are listed in Table S1.…”

Wnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications

“…This anti-atherogenic role of XAV939 is associated with the inhibition of nuclear translocation of β-catenin [53]. Inhibition of tankyrase activity by XAV939 was shown to suppress isoproterenol-induced hyperactivation of the Wnt/β-catenin pathway and provide protection against isoproterenol-induced ventricular dilatation in an adult zebrafish model [54] (Table 1).…”