Cardioprotection of an I channel agonist on L-thyroxine induced rat ventricular remodeling.

Downregulation of inward rectifier potassium (I) channel is a hallmark in cardiac hypertrophy and failure. The cardioprotection of zacopride (a selective I agonist) and underlying mechanisms were investigated in L-thyroxine (T4) or Triiodothyronine (T3)-induced cardiac remodeling. In the study, adult male Sprague-Dawley (SD) rats were randomly divided into control, L-thyroxine, L-thy+zacopride, and L-thy+zacopride+chloroquine (an I antagonist) groups. Echocardiography, histopathology, TUNEL assay, western blotting and confocal imaging for intracellular Ca fluorescence were performed. In the study, zacopride and nifedipine (a LTCC blocker) were used to compare their effects on Kir2.1, SAP97, autophagy, and [Ca] 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 I, SAP97, and [Ca] homeostasis in cardiomyocytes. I antagonist chloroquine or BaCl reversed these effects. Nifedipine could attenuate intracellular Ca overload with no significant effects on I, 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 I-dependent manner.