Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice.
BACKGROUND
Maintaining physiological levels of hydrogen sulfide during ischemia is necessary to limit injury to the heart. Because of the anti-inflammatory effects of hydrogen sulfide, we proposed that the hydrogen sulfide donor, sodium sulfide (Na2S), would attenuate myocardial injury through upregulation of protective microRNA-21 (miR-21) and suppression of the inflammasome, a macromolecular structure that amplifies inflammation and mediates further injury.


RESULTS
Na2S-induced miR-21 expression was measured by quantitative polymerase chain reaction in adult primary rat cardiomyocytes and in the mouse heart. We measured inflammasome formation and activity in cardiomyocytes challenged with lipopolysaccharide and ATP or simulated ischemia/reoxygenation and in the heart after regional myocardial ischemia/reperfusion, in the presence or absence of Na2S. To assess the direct anti-inflammatory effects of hydrogen sulfide in vivo, we used 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 (-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%) after ischemia/reperfusion injury in vivo (all P<0.05). These protective effects were absent in cells treated with the miR-21 eraser, antagomiR-21, and in miR-21 knockout 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 knockout mice.


CONCLUSIONS
Na2S induces cardioprotective effects through miR-21-dependent attenuation of ischemic and inflammatory injury in cardiomyocytes.
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Stefano
S
Toldo
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Anindita
A
Das
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Eleonora
E
Mezzaroma
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Vinh Q
VQ
Chau
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Carlo
C
Marchetti
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
David
D
Durrant
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Arun
A
Samidurai
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Benjamin W
BW
Van Tassell
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Chang
C
Yin
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Ramzi A
RA
Ockaili
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Navin
N
Vigneshwar
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Nitai D
ND
Mukhopadhyay
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Rakesh C
RC
Kukreja
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.
Antonio
A
Abbate
From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond. fnsalloum@vcu.edu.
Fadi N
FN
Salloum
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism; D015854:Up-Regulation
C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D013440:Sulfides; C033479:sodium sulfide; D006862:Hydrogen Sulfide
hydrogen sulfide; inflammasomes; microRNAs; myocardial infarction