Abstract
Background/AimsSeptic cardiomyopathy is a severe condition that remains a challenge for clinical management. This study investigated whether the natural polyphenolic compound resveratrol could be used as a prophylactic treatment to alleviate sepsis-related myocardial injury; the underlying molecular mechanisms were deciphered by both in vitro and in vivo experiments.MethodsA mouse model of endotoxin-induced cardiomyopathy was developed by intraperitoneal injection of LPS, and resveratrol was administered prophylatically to the animals. Serum LDH and CK activities were measured to detect myocardial injury, and echocardiography was performed to monitor cardiac structure and function. Various cytokines/chemokines and the Nrf2 antioxidant defense system were examined in the heart tissue. The effects of resveratrol on LPS-induced Nrf2 activation, ROS generation, and apoptotic cell death were further investigated in cultured primary human cardiomyocytes. An Nrf2 specific siRNA was used to define its role in resveratrol-mediated cardiomyocyte protective effect.ResultsResveratrol pretreatment significantly attenuated LPS-induced myocardial injury in mice, which was associated with suppressed proinflammatory cytokine production and enhanced Nrf2 activation in the heart. In cultured primary human cardiomyocytes, resveratrol activated Nrf2, inhibited LPS-induced ROS generation, and effectively protected the cells from LPS-induced apoptotic cell death. Knockdown of Nrf2 abrogated resveratrol-mediated protection of the cells from LPS-induced cell death.ConclusionResveratrol effectively alleviates endotoxin-induced cardiac toxicity through mechanisms that involve the Nrf2 antioxidant defense pathway. Our data suggest that resveratrol might be developed as a useful prophylactic management for septic cardiomyopathy.
Highlights
Septic shock is a syndrome of sepsis-induced organ failure and hypotension
Apoptosis represents a hallmark of cardiomyocyte injury due to endotoxin exposure during sepsis, and its critical role has been well recognized in the initiation and development of heart failure
By utilizing a mouse model, we demonstrated that resveratrol treatment significantly attenuated LPS-induced myocardial injury in mice, which was associated with suppressed proinflammatory cytokine production and enhanced nuclear erythroid-related factor 2 (Nrf2) activation in the heart
Summary
Severe fatal hypotension and heart failure is one of the characteristics of septic shock. Depression of both left and right ventricular function and drop in left ventricle ejection fraction can occur during septic shock [1]. Cardiac depression in septic shock makes a complex clinical syndrome as it is difficult to maintain cardiac output. These resulted in reflex tachycardia and other compensatory physiological process to maintain systemic arterial blood pressure [2]. Patients with sepsis with lower left ventricular ejection fraction have increased plasma level of TNFa and apoptotic cell death of cardiomyocytes [3]. Apoptosis represents a hallmark of cardiomyocyte injury due to endotoxin exposure during sepsis, and its critical role has been well recognized in the initiation and development of heart failure
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