Induction of MicroRNA-21 With Exogenous Hydrogen Sulfide Attenuates Myocardial Ischemic and Inflammatory Injury in Mice

Abstract

Background Maintaining physiological levels of hydrogen sulfide (H2S) during ischemia is necessary to limit injury to the heart. Due to the anti-inflammatory effects of H2S, we proposed that the H2S donor, Na2S, would attenuate myocardial injury through upregulation of ‘protective’ microRNA (miR)-21 and suppression of the inflammasome, a macromolecular structure that amplifies inflammation and mediates further injury. Methods and Results Na2S-induced miR-21 expression was measured by qPCR in adult primary rat cardiomyocytes and in the mouse heart. We measured inflammasome formation and activity in cardiomyocytes challenged with lipopolysaccharide (LPS) and adenosine-tri-phosphate (ATP) or simulated ischemia/reoxygenation; and in the heart following regional myocardial ischemia/reperfusion (I/R), in the presence or absence of Na2S. To assess the direct anti-inflammatory effects of H2S in vivo, we utilized a peritonitis model by way of intraperitoneal injection of zymosan A. Na2S attenuated inflammasome formation and activity - measured by counting cytoplasmic aggregates of the scaffold protein Apoptosis Speck-like protein containing a Caspase-recruitment domain (ASC; −57%) and caspase-1 activity (−50%) in isolated cardiomyocytes and in the mouse heart (all P<0.05). Na2S also inhibited apoptosis (−38%) and necrosis (−43%) in cardiomyocytes in vitro and reduced myocardial infarct size (−63%) following I/R injury in vivo (all P<0.05). These protective effects were absent in cells treated with antagomiR-21 and in miR-21 KO mice. Na2S also limited the severity of inflammasome-dependent inflammation in the model of peritonitis (P<0.05) in wild-type but not in miR-21 KO mice. Conclusions Na2S induces cardioprotective effects through miR-21-dependent attenuation of ischemic and inflammatory injury in cardiomyocytes.

miRNA-30 Family Inhibition Protects Against Cardiac Ischemic Injury by Regulating Cystathionine-γ-Lyase Expression

“…Thus far, there have been only a few publications that have delineated the relationship between miRNAs and H 2 S production. Yang et al (44) have observed that miR-21 represses human SP1 protein expression by targeting the 3¢-UTRs of the SP1 gene in SMCs, which, in turn, downregulates CSE mRNA expression and indirectly reduces H 2 S production; this was confirmed by Cindrova-Davies et al (7) and Toldo et al (34). In this work, we provided novel evidence that the miR-30 family was able to regulate H 2 S production by directly targeting CSE.…”

Myocardial connexin-43 and PKC signalling are involved in adaptation of the heart to irradiation-induced injury: Implication of miR-1 and miR-21

“…They regulate the expression of extracellular matrix metalloproteinase-2 (MMP-2) (Bauersachs 2012). In contrast with the detrimental effects of over-expression of miR-21 in cardiac fibroblasts there is evidence that up-regulation of myocardial miR-21 early after myocardial infarction confers the cardioprotection by suppressing apoptosis, inflammation and necrosis hence promoting survival (Yin et al 2009;Bauersachs 2012;Quin et al 2012;Toldo et al 2014). Nevertheless, it remains unknown whether the expression of miR-21in the heart is altered following irradiation.…”

MicroRNA-21-Regulated Activation of the Akt Pathway Participates in the Protective Effects of H₂S against Liver Ischemia–Reperfusion Injury

“…21) Therefore, we applied an in situ hybridization assay to detect and localize the expression of miR-21 in livers. I/R elevated the in situ signals in rat livers compared with sham operation; GYY4137 further significantly increased, while PAG reduced, the in situ signals in I/R livers (Fig.…”

“…6,17,21) Several H 2 S-releasing drugs have demonstrated a considerable promise because of its safety and effectiveness in the management of many disorders in animal experiments, and have been evaluated in clinical trials. 2) In agreement with the present results, H 2 S has displayed protective activities against the injury to several organs including the heart, 17,21) liver 9) and brain, 4) induced by I/R, and lung injury induced by various factors.…”

“…PTEN, a known miR-21 target, is a well characterized phosphatase that inhibits Akt activation. 21) By downregulating PTEN, miR-21 promotes the activation of the Akt pathway. 13,19) However, exogenous H 2 S could restore the activation of Akt pathway by downregulating PTEN via increasing the expression of miR-21.…”