Cardioprotective potential of sulfated glycosaminoglycan from Amphioctopus marginatus against cardiotoxin-induced toxicity in human iPSC-derived cardiomyocytes.

Sulfated glycosaminoglycans, a group of structurally diverse polysaccharides found in the extracellular matrix of marine animal tissues, are recognized for their broad pharmacological potential. This study examines the cardioprotective potential of AMP-3, a sulfated glycosaminoglycan derived from the marine octopus Amphioctopus marginatus, focusing on its ability to mitigate myocardial dysfunction triggered by mitochondrial impairment, disrupted calcium homeostasis, and the resulting DNA damage in cardiomyocytes. AMP-3 (100 μg/mL) significantly improved myocardial function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSCs), reducing ATP depletion to 38.7 % and producing a four-fold increase in mitochondrial membrane potential (Δψ). Additionally, AMP-3 promoted a notable increase of 273 μm in 3D cardiosphere diameter, comparable to the standard drug liraglutide of 290 μm increase, and reduced intracellular [Ca2+] levels by 98.6 %, restoring calcium homeostasis. DNA damage was reduced by 73.7 %, further highlighting the antiapoptotic effects of the compound. Structure-activity analysis indicated that the higher uronic acid content (⁓23 %), degree of sulfation (⁓10 %) and the presence of (1→3)/(1→4)-glycosidic linkages with C-3 sulfation at β-GlcNAcp in AMP-3 may contribute to its promising cardioprotective effects, a conclusion further supported by ADME studies. These findings indicate that AMP-3 is a promising bioactive lead with notable cardioprotective potential, offering a multifaceted therapeutic strategy for improving cardiovascular health.