Abstract
BackgroundSepsis is a common disease that continues to increase in incidence in the world. Diseases, such as diabetes mellitus, may make the situation worse. Diabetic patients are at increased risk for common infections. This study was designed to investigate the role of glibenclamide on myocardial injury by lipopolysaccharides (LPS) in streptozotocin induced diabetic mice (STZ-mice).MethodsLPS was used to induce endotoxemia in STZ-mice. Heart rate and mean arterial pressure were measured by MPA-HBBS. Serum epinephrine level was measured by enzyme-linked immunosorbent assays (ELISA). Myocardial injury was examined by light and transmission electron microscope and TUNEL staining. Macrophage infiltration was measured by immunohistochemistry. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in myocardial tissue and serum in STZ-mice, and in conditional medium of primary cultured peritoneal macrophages were determined by ELISA. Nalp3 and Caspase-1 protein levels were measured by Western blotting analysis.ResultsSTZ administration decreased body weight and increased blood glucose in C57BL/6 mice. LPS injection caused decreases of heart rate and mean arterial pressure, and elevated serum epinephrine level in C57BL/6 mice. Compared with control mice without STZ treatment, LPS induced more severe myocardial injury and macrophage infiltration in STZ-mice, which was attenuated by pretreatment of glibenclamide. LPS stimulation enhanced the levels of IL-1β and TNF-α in both cardiac tissue and serum. Glibenclamide pretreatment significantly inhibited the serum levels of pro-inflammatory cytokines. Either high glucose or LPS increased the levels of IL-1β and TNF-α in the conditional medium of peritoneal macrophages. Glibenclamide treatment suppressed the increase of IL-1β level induced by high glucose and LPS. Furthermore, Nalp3 and Caspase-1 levels were markedly increased by high glucose plus LPS, and both proteins were significantly inhibited by glibenclamide treatment.ConclusionsWe conclude that glibenclamide could attenuate myocardial injury induced by LPS challenge in STZ-mice, which was possibly related to inhibiting inflammation through Nalp3 inflammasomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-014-0106-y) contains supplementary material, which is available to authorized users.
Highlights
Septic shock induced by bacteremia is one of the leading causes of death in critical patients
Hyperactivation of the immune response leads to the excessive production of various pro-inflammatory cytokines (IL-1β and tumor necrosis factor-α (TNF-α)) and cellular injury [4], which can result in a systemic inflammatory response and eventually lead to multiple organ failure and death
Glibenclamide did not modify body weight and blood glucose level in STZ-mice As shown in Figure 1, mice were rendered diabetic by the injection of STZ (60 mg/kg, i.p, ×5 d), and administered by oral gavage glibenclamide (5 mg/kg) for 14 days
Summary
Septic shock induced by bacteremia is one of the leading causes of death in critical patients. Activation of inflammatory factors in septic shock always occurs as a simultaneous immune response program initiated early in the course of the disease. Such as endotoxemia, this occurs frequently in septic shock, cause to hemorrhages, necrosis of the kidneys, and myocardial dysfunction. Lipopolysaccharide (LPS) is considered the principal cause responsible for the heart failure in sepsis shock. Sepsis is a common disease that continues to increase in incidence in the world. Diseases, such as diabetes mellitus, may make the situation worse. This study was designed to investigate the role of glibenclamide on myocardial injury by lipopolysaccharides (LPS) in streptozotocin induced diabetic mice (STZ-mice)
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