Red blood cell eNOS is cardioprotective in acute myocardial infarction
Miriam M. Cortese-Krott,
Tatsiana Suvorava,
Francesca Leo,
Sophia K. Heuser,
Anthea LoBue,
Junjie Li,
Stefanie Becher,
Rebekka Schneckmann,
Tanu Srivrastava,
Ralf Erkens,
Georg Wolff,
Joachim P. Schmitt,
Maria Grandoch,
Jon O. Lundberg,
John Pernow,
Brant E. Isakson,
Eddie Weitzberg,
Malte Kelm
Affiliations
Miriam M. Cortese-Krott
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Corresponding author. Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine-University of Düsseldorf Postfach, 128, Universitaetsstrasse 1, 40225, Düsseldorf, Germany.
Tatsiana Suvorava
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Francesca Leo
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Sophia K. Heuser
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Anthea LoBue
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Junjie Li
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Stefanie Becher
Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Rebekka Schneckmann
Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University, Germany
Tanu Srivrastava
Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University, Germany
Ralf Erkens
Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Georg Wolff
Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Joachim P. Schmitt
Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University, Germany
Maria Grandoch
Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University, Germany
Jon O. Lundberg
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
John Pernow
Department of Cardiology, Karolinska Institute, Stockholm, Sweden
Brant E. Isakson
Robert M. Berne Cardiovascular Research Center, Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, USA
Eddie Weitzberg
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
Malte Kelm
Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Red blood cells (RBCs) were shown to transport and release nitric oxide (NO) bioactivity and carry an endothelial NO synthase (eNOS). However, the pathophysiological significance of RBC eNOS for cardioprotection in vivo is unknown. Here we aimed to analyze the role of RBC eNOS in the regulation of coronary blood flow, cardiac performance, and acute myocardial infarction (AMI) in vivo. To specifically distinguish the role of RBC eNOS from the endothelial cell (EC) eNOS, we generated RBC- and EC-specific knock-out (KO) and knock-in (KI) mice by Cre-induced inactivation or reactivation of eNOS. We found that RBC eNOS KO mice had fully preserved coronary dilatory responses and LV function. Instead, EC eNOS KO mice had a decreased coronary flow response in isolated perfused hearts and an increased LV developed pressure in response to elevated arterial pressure, while stroke volume was preserved. Interestingly, RBC eNOS KO showed a significantly increased infarct size and aggravated LV dysfunction with decreased stroke volume and cardiac output. This is consistent with reduced NO bioavailability and oxygen delivery capacity in RBC eNOS KOs. Crucially, RBC eNOS KI mice had decreased infarct size and preserved LV function after AMI. In contrast, EC eNOS KO and EC eNOS KI had no differences in infarct size or LV dysfunction after AMI, as compared to the controls. These data demonstrate that EC eNOS controls coronary vasodilator function, but does not directly affect infarct size, while RBC eNOS limits infarct size in AMI. Therefore, RBC eNOS signaling may represent a novel target for interventions in ischemia/reperfusion after myocardial infarction.
