Cardioprotection of an I_K1 channel agonist on L-thyroxine induced rat ventricular remodeling

Downregulation of inward rectifier potassium (I_K1) channel is a hallmark in cardiac hypertrophy and failure. The cardioprotection of zacopride (a selective I_K1 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 I_K1 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 I_K1, SAP97, and [Ca²⁺]_i homeostasis in cardiomyocytes. I_K1 antagonist chloroquine or BaCl₂ reversed these effects. Nifedipine could attenuate intracellular Ca²⁺ overload with no significant effects on I_K1, 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_K1-dependent manner.