Abstract
Background: Heart failure is the leading cause of morbidity and mortality in economically developed countries. Proinflammatory cytokines play an important role in the pathogenesis of chronic heart failure, with circulating levels related to the severity and prognosis of the disease. We have previously reported that incomplete degradation of mitochondrial DNA by lysosomal DNase II results in the initiation of inflammation and development of heart failure. However, the mechanisms responsible for maintaining inflammatory responses within failing hearts remain poorly defined.
Methods and results: Here, we show that Regnase-1, an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs, determines the time course of cardiac inflammation and consequent development of heart failure in response to pressure overload. Cardiac-specific deletion of Regnase-1 showed no cardiac phenotypes under baseline conditions, but caused severe inflammation accompanied by a specific increase in the level of interleukin-6 (Il6) mRNA and dilated cardiomyopathy after 4 weeks of pressure overload. The mRNA level of Il6 in control hearts was transiently increased, but returned to the baseline by 1 week after operation, whereas that in Regnase-1-deficient hearts increased until 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in Regnase-1-deficient mice. Furthermore, adeno-associated virus 9-mediated cardiomyocyte-targeted gene delivery of Regnase-1 decreased myocardial Il6 mRNA level, improving cardiac dysfunction and inflammation in severe pressure overloaded wild-type hearts.
Conclusion: These findings indicate that the degradation of Il6 mRNA, as well as mitochondrial DNA, in cardiomyocytes is critical for restraining inflammation in failing hearts.
Methods and results: Here, we show that Regnase-1, an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs, determines the time course of cardiac inflammation and consequent development of heart failure in response to pressure overload. Cardiac-specific deletion of Regnase-1 showed no cardiac phenotypes under baseline conditions, but caused severe inflammation accompanied by a specific increase in the level of interleukin-6 (Il6) mRNA and dilated cardiomyopathy after 4 weeks of pressure overload. The mRNA level of Il6 in control hearts was transiently increased, but returned to the baseline by 1 week after operation, whereas that in Regnase-1-deficient hearts increased until 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in Regnase-1-deficient mice. Furthermore, adeno-associated virus 9-mediated cardiomyocyte-targeted gene delivery of Regnase-1 decreased myocardial Il6 mRNA level, improving cardiac dysfunction and inflammation in severe pressure overloaded wild-type hearts.
Conclusion: These findings indicate that the degradation of Il6 mRNA, as well as mitochondrial DNA, in cardiomyocytes is critical for restraining inflammation in failing hearts.
| Original language | English |
|---|---|
| Pages (from-to) | 44-45 |
| Number of pages | 2 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 120 |
| Early online date | 4 Aug 2018 |
| DOIs | |
| Publication status | Published - 2018 |