Downregulation of inward rectifier potassium (IK1) channel is a hallmark in cardiac hypertrophy and failure. The cardioprotection of zacopride (a selective IK1 agonist) and underlying mechanisms were investigated in L-thyroxine (T4) or Triiodothyronine (T3)-induced cardiac remodeling. In the in vivo study, adult male Sprague-Dawley (SD) rats were randomly divided into control, L-thyroxine, L-thy+zacopride, and L-thy+zacopride+chloroquine (an IK1 antagonist) groups. Echocardiography, histopathology, TUNEL assay, western blotting and confocal imaging for intracellular Ca2+ fluorescence were performed. In the in vitro study, zacopride and nifedipine (a LTCC blocker) were used to compare their effects on Kir2.1, SAP97, autophagy, and [Ca2+]i in H9C2 (2-1) cardiomyocytes. Zacopride treatment attenuated L-thyroxine- or T3 induced cardiac remodeling and dysfunction which manifested as cardiac hypertrophy and collagen deposition, dilated ventricle, decreased ejection fraction (EF), increased cardiomyocytes apoptosis, hyper-activation of CaMKII and PI3K/Akt/mTOR signaling, decreased cardiac autophagy, and increased expression of integrin β3. The cardioprotection of zacopride is strongly associated with the upregulation of IK1, SAP97, and [Ca2+]i homeostasis in cardiomyocytes. IK1 antagonist chloroquine or BaCl2 reversed these effects. Nifedipine could attenuate intracellular Ca2+ overload with no significant effects on IK1, SAP97, and autophagy. This study showed that zacopride could improve cardiac remodeling via facilitating Kir2.1 forward trafficking, and negatively regulating calcium-activated and PI3K/Akt/mTOR signalings, in an IK1-dependent manner.
Keywords: Inward rectifier potassium channel; L-thyroxine; PI3K; autophagy; calcium overload; cardiac remodeling.
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