Luteolin Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Modulating AMPK/HO-1-Mediated Oxidative Stress and Inflammatory Responses

Abstract Luteolin is a naturally occurring flavonoid with antioxidant and anti-inflammatory properties; however, its molecular regulation of pathological cardiac hypertrophy remains incompletely understood. Here, we investigated the effects and mechanisms of luteolin in an isoproterenol (ISO)-induced model of cardiac hypertrophy using male Sprague-Dawley rats and H9c2 cardiomyoblasts. Luteolin treatment attenuated ISO-induced cardiac hypertrophy, ventricular wall thickening, cardiomyocyte enlargement, collagen deposition, and the expression of hypertrophic markers. In parallel, luteolin reduced inflammatory cytokine production and oxidative stress in both animal and cellular models. Mechanistic experiments demonstrated that luteolin restored AMP-activated protein kinase (AMPK) phosphorylation and enhanced heme oxygenase-1 (HO-1) expression. Pharmacological inhibition and siRNA-mediated silencing of AMPK or HO-1 partially abolished the protective effects of luteolin against hypertrophic responses, inflammation, and oxidative injury. Time-course analysis further indicated that AMPK activation preceded HO-1 induction, supporting a potential AMPK/HO-1 signaling cascade. Collectively, these findings reveal that luteolin protects against β-adrenergic stress-induced cardiac remodeling through regulation of inflammatory and oxidative responses and identify AMPK/HO-1 signaling as an important molecular mechanism underlying its cardioprotective effects.