Journal Article

Adropin/Tirzepatide Combination Mitigates Cardiac Metabolic Aberrations in a Rat Model of Polycystic Ovarian Syndrome, Implicating the Role of the AKT/GSK3β/NF-κB/NLRP3 Pathway

El-Horany, Hemat El-sayed, Abdallah, Hanan M., Fouda, Mohamed H., Emam, Marwa Nagy, ElEsawy, Rasha Osama, Elseady, Walaa S., Abdelkader, Gamaleldien Elsayed, Abd El Maged, Amira M., Abd-Ellatif, Rania Nagi, Hafez, Yasser Mostafa, Nasef, Nahla Anas, Radwan, Doaa A., Hassan, Maha Elsayed, Hegab, Islam Ibrahim, Hassan, Shereen, Okasha, Asmaa H., Mansour, Nouran Mostafa

2025

Overview

Polycystic ovarian syndrome (PCOS) is a multifaceted metabolic and hormonal disorder in females of reproductive age, frequently associated with cardiac disturbances. This research aimed to explore the protective potential of adropin and/or tirzepatide (Tirze) on cardiometabolic aberrations in the letrozole-induced PCOS model. Female Wistar non-pregnant rats were allotted into five groups: CON; PCOS; PCOS + adropin; PCOS + Tirze; and PCOS + adropin+ Tirze. The serum sex hormones, glucose, and lipid profiles were securitized. Cardiac phosphorylated levels of AKT(pAKT), glycogen synthase kinase-3 beta (pGSK-3β), NOD-like receptor family pyrin domain containing 3 (NLPR3), IL-1β and IL-18 were assayed. The cardiac redox status and endoplasmic reticulum stress (ER) parameters including relative glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) gene expressions were detected. Finally, the immunoreactivity of cardiac NF-κB, Bcl2, and BAX were assessed. Our results displayed that adropin and/or Tirze intervention successfully alleviated the PCOS-provoked cardiometabolic derangements with better results recorded for the combination treatment. The synergistic effect of adropin and Tirze is mostly mediated via activating the cardiac Akt, which dampens the GSK3β/NF-κB/NLRP3 signaling pathway, with a sequel of alleviating oxidative damage, inflammatory response, ER stress, and related apoptosis, making them alluring desirable therapeutic targets in PCOS-associated cardiac complications.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Antidiabetics / Biomarkers / Blood Proteins / Cardiovascular disease / Dextrose / Diabetes / Disease Models, Animal / Endoplasmic Reticulum Stress - drug effects / Enzymes / Female / Follicles / Gene expression / Glucose / Glycogen / Glycogen Synthase Kinase 3 beta - metabolism / Health aspects / Homeostasis / Hormones, Sex / Insulin resistance / Lipids / Metabolism / Microbiota / Myocardium - metabolism / NF-kappa B - metabolism / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Ovaries / Pathogenesis / Peptides / Peptides - pharmacology / Polycystic ovary syndrome / Polycystic Ovary Syndrome - drug therapy / Polycystic Ovary Syndrome - metabolism / Proto-Oncogene Proteins c-akt - metabolism / Rats / Rats, Wistar / Signal Transduction - drug effects / Stein-Leventhal syndrome / Synthesis / Tirzepatide