Multiomics Analysis Reveals the Protective Effect of a Novel Bioactive Peptide (BP1) in Cardiomyopathy Using a Zebrafish Model

Medicinal plants have been used in traditional healthcare systems and drug discovery since ancient times, owing to their storage of natural products, including bioactive metabolites and peptides. Bioactive peptides (BPs) are reported to have diverse therapeutic potential and are used for the treatment/prevention of many lifelong diseases, including cardiovascular. In our previous work, we isolated and characterized a bioactive peptide, ASGLCPEEAVPRR (BP1), from Picrorhiza kurroa and hypothesized that BP1 possesses angiotensin-converting enzyme (ACE) inhibitory activity, which has a cardioprotective role; however, a system-level understanding of its cardioprotective and metabolic control is needed to validate the hypothesis. Here, we investigated the cardioprotective effect of BP1 in zebrafish larvae and adult models of isoproterenol (ISO)- and doxorubicin (DOX)-induced cardiac damage, respectively. Following the treatment, the cardiac morphology, cardiac functional parameters, transcriptome, and metabolome were studied. Results indicated that treatment with BP1 significantly reduced ISO-induced cardiac dysfunction in zebrafish larvae. Similarly, BP1 pretreatment effectively mitigated the DOX-induced pathological changes in the myocardium of zebrafish. Transcriptomic and weighted gene coexpression network analysis (WGCNA) showed attenuation in the expression of genes associated with protein synthesis, metabolic pathways, signaling pathways, and cardiac muscle contraction, among others, following BP1 treatment in the DOX-induced cardiotoxicity model. Untargeted metabolomics revealed metabolic pathways such as sphingolipid, riboflavin, and glutathione metabolism, among others, involved in attenuating DOX-induced cardiotoxicity by BP1. Our results concluded that BP1 treatment showed cardioprotection in zebrafish via targeting multiple pathogenic pathways involved in cardiotoxicity