Abstract 15836: Hydrogen Sulfide and MicroRNA-21: Possible Anti-inflammatory Partners in Heart
Background: Hydrogen sulfide (H2S) has been shown to possess anti-inflammatory effects in the setting of myocardial infarction (MI) and several inflammatory diseases. Since microRNA (miR)-21 has been implicated in inhibiting toll-like receptor signaling which is involved in the induction of inflammasome components, we examined whether miR-21 mediates the anti-inflammatory effects of H2S.
Methods and Results: In a classical pathway of inflammasome formation, adult primary rat cardiomyocytes (CM) were infected with empty virus or adenovirus encoding antagomiR-21 and then challenged with lipopolysaccharide (LPS; 100 ng/ml, for 2 h) and ATP (5 mM, for 1 h), in the presence or absence of the H2S donor, Na2S (10 μM). The aggregation of apoptosis speck-like protein containing a caspase-recruitment domain (ASC) was measured using immunofluorescence. To examine the effect of H2S in vivo, adult male C57BL or miR-21 knockout (KO) mice were treated with Na2S (100 μg/kg, ip) or vehicle (saline) 1 h prior to 30 min ischemia and 24 h reperfusion. The hearts were then harvested for assessment of ASC aggregates and caspase-1 activity (enzymatic assay). To test the effects of Na2S in a non-ischemic in vivo model, we treated mice with zymosan A (inflammasome activator; 30 mg/kg, ip) with or without Na2S and assessed peritoneal leukocyte infiltration. Compared to control CM, Na2S attenuated ASC aggregation (48% reduction) in CM challenged with LPS+ATP, but not in antagomiR-21-infected CM. Na2S also induced miR-21 (3-fold, P<0.05) and blunted inflammasome formation in the heart [ASC aggregates in the infarct zone (42% decline, P<0.05) and caspase-1 activity (Fig. A)] following myocardial I/R, which was absent in miR-21 KO mice. Moreover, Na2S attenuated peritoneal leukocyte infiltration following zymosan administration in C57BL, but not in miR-21 KO mice (Fig. B).
Conclusion: Hydrogen sulfide inhibits myocardial inflammasome formation through miR-21-dependent mechanism.
- © 2013 by American Heart Association, Inc.