Abstract
Ischemic heart disease remains a leading cause of morbidity and mortality in the United States. Interventional reperfusion induces further damage to the ischemic myocardium through neutrophil infiltration and acute inflammation. As caspase recruitment domain-containing protein 9 (CARD9) plays a critical role in innate immune response and inflammation, we hypothesized that CARD9 knockout would provide protection against ischemia and reperfusion (I/R) injury through attenuation of acute inflammatory responses. C57BL/6 wild-type (WT) and CARD9-/- mice were subjected to 45 min left anterior descending (LAD) coronary artery occlusion followed by 24-h reperfusion. Area at risk (AAR) and infarct size were measured by Evans blue and triphenyltetrazolium chloride (TTC) staining. Frozen heart sections were stained with anti-mouse GR-1 antibody to detect infiltrated neutrophils. Concentrations of cytokines/chemokines TNF-α, IL-6, CXCL-1 and MCP-1 were determined in heart tissue homogenate and serum by ELISA assay. Western immunoblotting analyses were performed to measure the phosphorylation of p38 MAPK. Our results indicate that following I/R, infarct size was significantly smaller in CARD9-/- mice compared to WT. The number of infiltrated neutrophils was significantly lower in CARD9-/- mice compared to WT. Levels of TNF-α, IL-6, CXCL-1 and MCP-1 were significantly reduced in heart tissue and serum from CARD9-/- mice compared to WT. CARD9-/- mice also exhibited significantly lower levels of phosphorylated p38 MAPK. Taken together, our results suggest that CARD9 knockout protects the heart from ischemia/reperfusion (I/R) injury, possibly through reduction of neutrophil infiltration and attenuation of CARD9-associated acute inflammatory signaling.
Highlights
Despite continued progress elucidating underlying mechanisms in ischemic heart disease, it remains the leading cause of morbidity and mortality worldwide [1,2,3,4]
We hypothesized that caspase recruitment domaincontaining protein 9 (CARD9) plays a detrimental role in the acute inflammatory responses associated with myocardial ischemia and reperfusion (I/R) injury
Infarct size was significantly smaller in the CARD9-/-+I/R than in the WT+I/R group demonstrating that CARD9 knockout protected the heart from I/R injury
Summary
Despite continued progress elucidating underlying mechanisms in ischemic heart disease, it remains the leading cause of morbidity and mortality worldwide [1,2,3,4]. Following acute ischemic insult, damaged and dying cardiomyocytes expel a melange of cytosolic materials including damage-associated molecular patterns (DAMPs) [5,6,7]. DAMPs are recognized by pattern recognition receptors (PRRs) of immune cells, activating a swift and severe local inflammatory response that induces further damage on the myocardial tissue at risk. Targeting the production of cytokines that propagate the inflammatory response and chemokines that attract infiltrating immune cells into the myocardium is emerging as a new frontier in the fight against I/R injury [8]. Neutrophils predominate the infiltrating immune cell population in the early inflammatory response following acute myocardial injury and provoke the greatest tissue damage [9, 10]. Even with an advanced understanding of the inflammatory signaling network, therapies targeting these inflammatory signals are still unable to prevent the injurious inflammatory response [7]
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