Rosmarinic acid protects against lipopolysaccharide-induced cardiac dysfunction via activating Sirt1/PGC-1α pathway to alleviate mitochondrial impairment

Background: Sepsis-induced cardiomyopathy is a decisive factor that plays a critical role in high mortality of septic patients in the critically ill. Mitochondrial dysfunction occurred during sepsis is a vital contributor to the pathogenesis of myocardial damage. Rosmarinic acid (RA), a natural poly-phenolic compound, has showed cardio-protective and mitochondrial-protective effect. However, the effect of RA in sepsis-induced cardiomyopathy remains unknown.

Material and method: Adult mice were subjected to intraperitoneal injection of saline (control) or lipopolysaccharide (LPS, 5 mg/kg) to mimic sepsis-induced cardiomyopathy. Immediately after LPS challenge, vehicle or RA (100 mg/kg/d) was administrated via gavage. Cardiac function was examined with echocardiographic analyses 12 hours after LPS challenge and cumulative survival of mice was recorded for 8 days. Heart tissues were harvested 12 hours after LPS challenge to perform histological analyses and determine mitochondrial function.

Results: RA significantly improved cardiac function and survival of LPS-injected mice. Histologically, RA attenuated LPS-mediated cardiomyocyte damage, indicated by decreased cardiomyocyte Apoptosis and improved myocardial swollen and disarrangement. Moreover, RA attenuated LPS-mediated myocardial mitochondrial dysfunction, indicated by improved mitochondrial ultrastructure, increased mitochondrial membrane potential (MMP), synthesis of Adenosine triphosphate (ATP), markedly decreased Reactive Oxygen Species (ROS) level and alleviated oxidative stress in heart tissues. RA treatment downregulated protein expression of SIRT1 and Peroxisome Proliferator-activated Receptor gamma coactivator-1α (PGC-1α), and SIRT1 inhibition blocked protective effect of RA on LPS-induced myocardial damage and mitochondrial dysfunction.

Conclusion: Collectively, RA attenuates LPS-induced cardiac dysfunction via activating SIRT1/PGC-1α pathway to alleviate mitochondrial impairment. It may be a promising cardio-protective drug to be used for septic patients. This article is protected by copyright. All rights reserved.

Sepsis; Sirt1; cardiac dysfunction; mitochondrial dysfunction, rosmarinic acid.