Reduction of gap and adherens junction proteins and intercalated disc structural remodeling in the hearts of mice submitted to severe cecal ligation and puncture sepsis*

Celes, Mara Rúbia Nunes; Torres-Dueñas, Diego; Alves-Filho, José C.; Duarte, Djane B.; Cunha, Fernando; Rossi, Marcos A.

doi:10.1097/01.ccm.0000281454.97901.01

Cited by 35 publications

(37 citation statements)

References 42 publications

(22 reference statements)

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“…The 14-day survival rate in CVB3-infected mice treated with atorvastatin 10 mg kg -1 day -1 was significantly higher than that in CVB3-infected mice treated with saline (log rank test, P \ 0.05) intercellular communication by proinflammatory mediators, including LPS, TNF-a, IL-1a, and IL-1b, has been found in endothelial cells, vascular smooth muscle cells, Schwann cells, astrocytes, and hepatocytes [20][21][22][23][24][25]. Furthermore, a significant downregulation of Cx43 mRNA and protein expression in myocardium has also been observed in severe septic injuries or LPS-induced endotoxemia [8,9]. However, one study reported that expression of Cx43 was increased in rat kidney and lungs after administration with bacteria LPS [26].…”

Section: Discussionmentioning

confidence: 88%

“…It has been suggested that proinflammatory mediators may regulate Cx expression at both transcriptional and posttranscriptional levels [26]. The in vitro experiments with rat myoblast cell line H9c2 found that the high levels of TNF-a detected in the serum from LPS-treated rats could downregulate Cx43 expression by inhibiting the promoter activity of Cx43 gene transfected to this cell line [8]. Although the precise mechanism warrants further study, an AP-1 site in its promoter is likely involved in the cytokine regulation of Cx43 [27].…”

Section: Discussionmentioning

confidence: 99%

“…For example, severe septic injury accompanied by high levels of tumor necrosis factor-a (TNF-a) and macrophage inflammatory protein-1a (MIP-1a) in septic focus and serum resulted in a marked reduction in Cx43 in left ventricles, leading to the loss of intercalated disc structural integrity [8]. Similarly lipopolysaccharide (LPS) administration significantly suppressed Cx43 expression in rat hearts [9].…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulation by atorvastatin upregulates expression of gap junction proteins in coxsackievirus B3 (CVB3)-induced myocarditis

Zhang

2009

Inflamm. Res.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunomodulation by atorvastatin upregulates expression of gap junction proteins in coxsackievirus B3 (CVB3)-induced myocarditis

Zhang

2009

Inflamm. Res.

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“…The latter is a well recognized phenomenon occurring after myocardial ischemia and may represent a response that is analogous to the myocardial "hibernation" that is postulated to occur in sepsis (13,14,18,49). Abnormalities in calcium homeostasis and defects in cardiomyocyte coupling due to abnormal cardiac gap junctions have also been proposed as potential causes of sepsis-induced cardiac depression (11,50). Although sepsis-induced myocardial suppression is occasionally lethal, moderate sepsis-induced "hibernation" could be advantageous by preventing stress-induced cardiac injury (1,18,49).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Takasu

Gaut

Watanabe

et al. 2013

Am J Respir Crit Care Med

395

315

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Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (,1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P , 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 6 9.5% and 32.3 6 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P , 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. Conclusions: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.Keywords: sepsis; apoptosis; necrosis; autophagy; kidney Sepsis causes profound myocardial depression, and echocardiography frequently reveals severe biventricular dysfunction (1-5). Sepsis also induces renal insufficiency in 30 to 60% of patients, up to half of whom require dialysis (6-10). The mechanistic basis for cardiac and renal dysfunction occurring in sepsis is controversial (1,5,7,9,(11)(12)(13)(14)(15)(16). The degree to which apoptosis, necrosis, or autophagy contribute to cardiac and renal dysfunction in sepsis is unresolved (2,3,(16)(17)(18)(19).Although a few well controlled studies have been performed, extensive cell death in hearts or kidneys in patients dying of sepsis has not been described, leading investigators to postulate that cellular "hibernation" or metabolic suppression and not cell death is the basis of sepsis-induced organ failure (11,13,14,16,18,(20)(21)(22). Cardiac dysfunction in sepsis is reversible, and the majority of renal failure patients who survive sepsis recover baseline renal function; these observations are consistent with organ "hibernation" (1, ...

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“…Taking into account that myocardial contractile function depends on ID for mechanical and electrical/chemical coupling of cardiomyocytes, the occurrence of ID changes in experimental CLP sepsis in mice was examined [111]. During sepsis, the ID was initially evaluated by analyzing the expression of connexin43 and N-cadherin.…”

Section: Loss Of the Structural Integrity Of Intercalated Discs In Exmentioning

confidence: 99%

Sepsis: Going to the Heart of the Matter

Celes

Prado

Rossi³

2012

Pathobiology

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Although myocardial depression is the predominant cause of death in severe sepsis/septic shock, it remains disputed whether the functional changes are a consequence of structural alterations. If we look at myocardial dysfunction from the perspective of a critically ill patient, there are a few questions to be asked: What causes myocardial dysfunction? What is the pathophysiology of cardiac dysfunction and death? Is there something that could be done to prevent the outcome? Each of these questions is interrelated and the answers will be more easily addressed if we continue to understand the basic mechanisms that are implicated. The principal mechanisms proposed for the pathogenesis of myocardial dysfunction support a prominent role for functional rather than anatomical abnormalities. However, attempts to reduce the high mortality in septic patients by manipulating the functional alterations have provided limited success. In recent years, the concept of septic cardiomyopathy has evolved, which implies alterations in the myocardial phenotype. This review includes an overview on the activation of the immune system and therapeutic approaches in sepsis, myocardial structural changes in the human septic heart, experimental models of sepsis, and cellular, molecular and functional myocardial changes seen in a variety of experimental sepsis models. The abnormal parameters discussed may emerge as therapeutic targets, for which modulation might provide beneficial effects on cardiovascular outcome and mortality in sepsis in the future.

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Reduction of gap and adherens junction proteins and intercalated disc structural remodeling in the hearts of mice submitted to severe cecal ligation and puncture sepsis*

Cited by 35 publications

References 42 publications

Immunomodulation by atorvastatin upregulates expression of gap junction proteins in coxsackievirus B3 (CVB3)-induced myocarditis

Immunomodulation by atorvastatin upregulates expression of gap junction proteins in coxsackievirus B3 (CVB3)-induced myocarditis

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Sepsis: Going to the Heart of the Matter

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