Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase

Cho Kai Wu, Jen Kuang Lee, Fu Tien Chiang, Chic Hsin Yang, Shui Wei Huang, Juey Jen Hwang, Jiunn Lee Lin, Chuen Den Tseng, Jin Jer Chen, Chia Ti Tsai

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Abstract

OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p <.01 for each) were found for tumor necrosis factor-α and E/Em (r =.87) and E/A (r =-0.69), and for interleukin-6 and E/Em (r =.80) and E/A (r =-0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.

Original languageEnglish
Pages (from-to)984-992
Number of pages9
JournalCritical Care Medicine
Volume39
Issue number5
DOIs
Publication statusPublished - Jan 1 2011
Externally publishedYes

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Diastolic Heart Failure
Calcium-Transporting ATPases
Sarcoplasmic Reticulum
Interleukin-6
Down-Regulation
Tumor Necrosis Factor-alpha
Critical Illness
Cardiac Myocytes
Cytokines
Calcium
Gene Expression
Hospital Laboratories
Luciferases
Population Groups
Intensive Care Units
Adenosine Triphosphatases
Echocardiography
Cohort Studies
Phenotype
Mortality

Keywords

  • cytokines
  • diastolic heart failure
  • HL-1 cardiomyocytes
  • inflammation

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase. / Wu, Cho Kai; Lee, Jen Kuang; Chiang, Fu Tien; Yang, Chic Hsin; Huang, Shui Wei; Hwang, Juey Jen; Lin, Jiunn Lee; Tseng, Chuen Den; Chen, Jin Jer; Tsai, Chia Ti.

In: Critical Care Medicine, Vol. 39, No. 5, 01.01.2011, p. 984-992.

Research output: Contribution to journalArticle

Wu, Cho Kai ; Lee, Jen Kuang ; Chiang, Fu Tien ; Yang, Chic Hsin ; Huang, Shui Wei ; Hwang, Juey Jen ; Lin, Jiunn Lee ; Tseng, Chuen Den ; Chen, Jin Jer ; Tsai, Chia Ti. / Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase. In: Critical Care Medicine. 2011 ; Vol. 39, No. 5. pp. 984-992.
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AU - Yang, Chic Hsin

AU - Huang, Shui Wei

AU - Hwang, Juey Jen

AU - Lin, Jiunn Lee

AU - Tseng, Chuen Den

AU - Chen, Jin Jer

AU - Tsai, Chia Ti

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N2 - OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p <.01 for each) were found for tumor necrosis factor-α and E/Em (r =.87) and E/A (r =-0.69), and for interleukin-6 and E/Em (r =.80) and E/A (r =-0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.

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