Abstract
Forkhead box protein P1 (Foxp1) exerts an extensive array of physiological and pathophysiological impacts on the cardiovascular system. However, the exact function of myocardial Foxp1 in myocardial ischemic reperfusion injury (MIRI) stays largely vague. The hypoxia reoxygenation model of H9c2 cells (the rat ventricular myoblasts) closely mimics myocardial ischemia-reperfusion injury. This report intends to research the effects and mechanisms underlying Foxp1 on H9c2 cells in response to hypoxia (12 h)/reoxygenation (4 h) (HR) stimulation. Expressions of Foxp1 and Phosphatidylinositol 3-kinase interacting protein 1 (Pik3ip1) were both upregulated in ischemia/reperfusion (IR)/HR-induced injury. Stimulation through HR led to marked increases in cellular apoptosis, mitochondrial dysfunction, and superoxide generation in H9c2 cells, which were rescued with knockdown of Foxp1 by siRNA. Silence of Foxp1 depressed expression of Pik3ip1 directly activated the PI3K/Akt/eNOS pathway and promoted nitric oxide (NO) release. Moreover, the knockdown of Foxp1 blunted HR-induced enhancement of reactive oxygen species (ROS) generation, thus alleviating excessive persistence of mitochondrial permeability transition pore (mPTP) opening and decreased mitochondrial apoptosis-associated protein expressions in H9c2 cells. Meanwhile, these cardioprotective effects can be abolished by LY294002, NG-nitro-L-arginine methyl ester (L-NAME), and Atractyloside (ATR), respectively. In summary, our findings indicated that knockdown of Foxp1 prevented HR-induced encouragement of apoptosis and oxidative stress via PI3K/Akt/eNOS signaling activation by targeting Pik3ip1 and improved mitochondrial function by inhibiting ROS-mediated mPTP opening. Inhibition of Foxp1 may be a promising therapeutic avenue for MIRI.