Aurantiamide Acetate Mitigates Hypertensive Cardiac Hypertrophy via Modulation of MAPK Signaling and ER Stress

Purpose Hypertensive cardiac hypertrophy contributes significantly to heart failure and is mediated by maladaptive mechanisms including mitogen-activated protein kinase (MAPK) signaling and endoplasmic reticulum (ER) stress. Aurantiamide acetate (AA), a dipeptide derivative derived from edible plants and marine fungi, exhibits anti-inflammatory and vasoprotective effects. However, its impact on hypertensive cardiac hypertrophy remains unclear. This study aims to explore the therapeutic potential of AA in mitigating cardiac hypertrophy by targeting MAPK signaling and ER stress pathways. Methods Cellular hypertrophy was induced in H9C2 cardiomyoblasts using angiotensin II (Ang II), and tunicamycin (TM) was used to trigger ER stress. AA’s effects were assessed via viability assays, immunofluorescence staining, and ELISA for hypertrophic and ER stress markers. In vivo, hypertensive hypertrophic cardiomyopathy (HCM) was established in rats using a two-kidney, one-clip (2K1C) model, followed by AA administration. Cardiac hypertrophy, fibrosis, MAPK activation, and ER stress markers were evaluated histologically and biochemically. Results In vitro, AA significantly reduced Ang II-induced cardiomyocyte hypertrophy and ER stress, as evidenced by decreased cell size, atrial natriuretic peptide (ANP) expression, and glucose-regulated protein 78 (GRP78) levels. In vivo, AA ameliorated hypertension-induced cardiac remodelling, reduced myocardial fibrosis, suppressed MAPK phosphorylation (p38, extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK]), and alleviated ER stress. Blood pressure and serum Ang II levels were also significantly lowered in AA-treated rats. Conclusion Aurantiamide acetate mitigates hypertensive cardiac hypertrophy by inhibiting MAPK activation and ER stress both in vitro and in vivo, highlighting its potential as a novel therapeutic agent for hypertensive heart disease.