Pituitary adenylate cyclase-activating polypeptide (PACAP) attenuates diabetic cardiomyopathy via Nrf2/HO-1 antioxidant signaling and NF-κB-mediated inflammation suppression in streptozotocin-treated mice

Abstract

Diabetic cardiomyopathy (DCM), characterized by oxidative stress, inflammation, and pathological remodeling, is still a primary cause of death in diabetes. This study examines how pituitary adenylate cyclase-activating polypeptide (PACAP) might treat diabetic heart dysfunction caused by streptozotocin (STZ), with an emphasis on modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant axis and NF-κB-mediated inflammatory signaling. STZ treatment reduced PACAP expression in serum and cardiac tissues, associated with impaired ventricular contractility and hypertrophy. PACAP treatment reversed these effects, restoring heart function, as shown by increased ejection fraction and fractional shortening. PACAP also reduced cardiac hypertrophy, indicated by decreased cardiomyocyte cross-sectional area and heart weight-to-tibia length ratios. Serum markers of myocardial damage (CK-MB, AST, LDH) were elevated in STZ-treated mice but decreased by PACAP. PACAP lowered hemodynamic stress, as shown by reduced mean arterial pressure. PACAP reduced oxidative damage by increasing antioxidant enzyme activity (catalase, SOD, and GPx) and lowering lipid peroxidation, while also inhibiting NADPH oxidase activity. PACAP reduced STZ-induced myocardial inflammation by lowering TNF-α, IL-6, and IL-1β levels and increasing IL-10 levels in cardiac tissue and serum, mitigating systemic inflammation. PACAP restored Nrf2/HO-1 expression and maintained IκBα, which inhibited NF-κB signaling. These findings suggest PACAP's potential to combat oxidative stress and inflammation in STZ-induced DCM, warranting further mechanistic and translational studies.