Resveratrol Alleviates Endotoxin-Induced Myocardial Toxicity via the Nrf2 Transcription Factor

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.

C1q/Tumor Necrosis Factor-Related Protein 9 Protects against Acute Myocardial Injury through an Adiponectin Receptor I-AMPK-Dependent Mechanism

“…Because inflammatory response and oxidative stress are associated with the development of cardiac injury and dysfunction in sepsis-induced cardiac dysfunction and other models of cardiac injury (21)(22)(23), mRNA levels of proinflammatory cytokines and NADPH oxidase components in the myocardium in CTRP9-KO and WT mice at 6 h after LPS administration were measured by real-time PCR methods. CTRP9-KO mice showed higher expression levels of proinflammatory cytokines, including TNF-␣, IL-6, IL-1␤, and MCP-1, and NADPH oxidase components, including gp91 phox , p67 phox , and p47 phox , compared to WT mice ( Fig.…”

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

“…However, inflammatory responses triggered by tissue damage should be transient and self-restricted. Instead, doxorubicin caused chronic and much more destructive inflammation that usually includes the activation of TNF signaling pathway, generation of massive ROS and persistent expression of multiple proinflammatory cytokines-all of which belong to typical characteristics of inflammatory responses against endotoxin (27,28). In addition, the central role of TLR4 in mediating this pathologic process-as demonstrated by both our and other studies-further suggests that endotoxin is the most likely antigen to trigger tissue inflammation, because the principal function of this receptor is to recognize the component of invaded bacteria, notably including endotoxin (17,29).…”

Resveratrol Is Active against Leishmania amazonensis: In Vitro Effect of Its Association with Amphotericin B

“…Our data, together with the literature, indicate that resveratrol inhibits NO, demonstrating that its antiamastigote activity is independent of NO production. Recently, it has been shown that resveratrol inhibits the oxidative activity induced by lipopolysaccharide (LPS) and paraquat by increasing the level of nuclear factor erythroidlike 2 (NFR2) (56,57). The inhibition of NO and ROS by resveratrol seems to be important for controlling infection by T. cruzi, a trypanosomatid protozoan, as for Leishmania infection.…”