Isoliensinine alleviates cardiac apoptosis by activating the PI3K/AKT Pathway: Insights from <em>in Vivo</em> and <em>in Vitro</em> Studies

This study investigated the cardioprotective effects of Isoliensinine, a bisbenzylisoquinoline alkaloid from <em>Nelumbo nucifera</em> Gaertn, and its underlying mechanisms. Spontaneous hypertensive rats (SHR) received Isoliensinine (2.5, 5, 10 mg/kg/day) or valsartan (10 mg/kg/day) for 10 weeks, with Wistar-Kyoto rats as controls. Cardiac function, histopathology, apoptosis, and transcriptomic changes were evaluated <em>in vivo</em> and in Angtension II (AngII)-stimulated H9c2 cardiomyocytes <em>in vitro</em>. Isoliensinine significantly improved left ventricular function, and ameliorated pathological cardiac damage in SHR. Transcriptomic analysis revealed that Isoliensinine reversed 111 up-regulated and 127 down-regulated transcripts in cardiac tissues of SHR, with enrichment of pathways related to apoptosis and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Both <em>in vivo</em> and <em>in vitro</em> experiments confirmed that Isoliensinine reduced cardiomyocyte apoptosis and restored PI3K/AKT phosphorylation. Cellular thermal shift assay (CETSA) and molecular docking supported potential binding of Isoliensinine to PI3K and AKT. Co-treatment with PI3K/AKT activator 740Y-P did not negate the effects of Isoliensinine, suggesting pathway specificity. These findings indicated that Isoliensinine alleviates hypertensive cardiac dysfunction by inhibiting cardiomyocyte apoptosis primarily through modulation of the PI3K/AKT pathway and may serve as a promising therapeutic agent for hypertension.