Sacubitril/Valsartan Ameliorates Inflammation and Oxidative Stress in Hypertensive Heart Disease by Upregulating <scp>CAMKK2</scp> Protein and Modulating the <scp>AMPK</scp>/<scp>AKT</scp>/<scp>GSK</scp>‐3β Axis

Sacubitril/valsartan (Sac/Val) has emerged as an effective compound with myocardium-protective functions in experimental and clinical trials for heart failure. This study investigated the function of Sac/Val in hypertensive heart disease (HHD) and explored the underlying mechanism. Spontaneous hypertensive rats (SHRs) were used as an animal model of HHD. Sac/Val administration ameliorated pathological injury, fibrosis, cell apoptosis, inflammatory cytokine production, and oxidative stress in the myocardial tissues of HHD rats. Similar findings were observed in vitro, where Sac/Val treatment reduced inflammation, oxidative stress, and fibrosis-related markers in Ang II-challenged H9C2 cells. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was identified as a target of Sac/Val which was downregulated in HHD models, and CAMKK2 protein levels were restored by Sac/Val treatment. Lentiviral vector-induced CAMKK2 knockdown reduced the phosphorylation levels of AMPKα, AKT, and GSK-3β, thereby negating the treatment effects of Sac/Val. Further treatment with AICAR, an AMPK agonist, significantly reactivated the AMPK/AKT/GSK-3β cascade and alleviated inflammatory injury in both models. Collectively, this study suggests that Sac/Val ameliorates inflammation and oxidative stress in HHD by restoring the CAMKK2 protein and activating the AMPK/AKT/GSK-3β cascade.