Cardioprotective role of phoenixin-14 in isoproterenol-induced myocardial injury: Involvement of AMPK, JAK2/STAT3, and Sema3E pathways

Abstract

Aims: This study aimed to evaluate the cardioprotective effects of phoenixin-14 (PNX-14) in isoproterenol (ISO)-induced myocardial infarction (MI) in rats, comparing both preventive and therapeutic administration. Materials and methods: Seventy adult male Wistar rats were divided into five groups: Control, PNX-14, ISO, ISO + PNX-14 (PNX-14 treatment after ISO), and PNX-14 + ISO (PNX-14 pretreatment before ISO). MI was induced by subcutaneous ISO (100 mg/kg/day) for two days. PNX-14 (5 nmol/kg, intraperitoneally) was administered once daily for 3 days. Biochemical, molecular, and histopathological analyses were performed to evaluate oxidative stress, inflammatory response, and apoptosis in cardiac tissue. Key findings: PNX-14 treatment significantly reduced the ISO-induced increases in heart/body weight ratio (0.54 +/- 0.05), infarct size (47.3 +/- 2.51 %), apoptotic index (40.8 +/- 2.99 %), and cardiac necrosis markers CK-MB and TnI (p < 0.001). It improved antioxidant defenses by increasing glutathione (GSH) and total antioxidant status (TAS), while reducing total oxidant status (TOS) and oxidative stress index (OSI). Pro-inflammatory cytokines TNF-alpha and IL-6 were lowered, and anti-inflammatory IL-10 increased. PNX-14 also attenuated apoptosis in cardiac tissue by downregulating cytochrome c, APAF-1, caspase-3, and Bax, and upregulating the anti-apoptotic marker Bcl-2. These effects were linked to modulation of Gpr173, AMPK/Nrf2/HO-1, and Sema3E/PlexinD1 pathways, alongside suppression of JAK2/STAT3 and NF-kappa B signaling. Furthermore, PNX-14 improved hemodynamic stability and histopathologically reduced ISO-induced myocardial damage. Significance: These results demonstrate that PNX-14, particularly when administered after injury, effectively attenuates myocardial damage through multi-pathway regulation of oxidative stress, inflammation, and apoptosis. PNX-14 may hold therapeutic potential for the prevention and treatment of cardiovascular diseases.