Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Platelet-derived microRNAs play a pivotal role in cardiac remodeling after myocardial ischemia

J. P. Schütte1, M.-C. Manke1, K. Hemmen2, B. Schörg3, S. Hoffmann3, G. Ramos4, M. Pogoda5, F. Kollotzek1, P. Münzer1, J. Pinnecker2, Y. Singh6, A. Mack7, B. Pichler3, F. Lang8, B. Nieswandt2, K. Heinze2, M. Gawaz9, N. Casadei5, O. Borst1

1Department of Cardiology, Angiology and Cardiovascular Medicine, DFG Heisenberg Group Thrombocardiology, University of Tübingen, Tübingen; 2Rudolf Virchow Center for Translational and Integrative Bioimaging, University of Würzburg, Würzburg; 3Department of Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, University of Tübingen, Tübingen; 4Department of Internal Medicine I, University Hospital of Würzburg, Würzburg; 5Institute of Medical Genetics and Applied Genomics, NGS Competence Center Tübingen, University of Tübingen, Tübingen; 6Institute of Medical Genetics and Applied Genomics, Institute of Physiology, University of Tübingen, Tübingen; 7Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen; 8Institute of Physiology, University of Tübingen, Tübingen; 9Department of Cardiology, Angiology and Cardiovascular Medicine, University of Tübingen, Tübingen;

Background: Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of the inflammatory response during myocardial ischemia and reperfusion (I/R). At the same time, platelets contain one of the broadest repertoires of miRNAs in terms of variety and relative abundance, which under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. The present study aimed to determine the role and unveil the regulatory function of platelet-derived miRNAs in myocardial injury and repair following myocardial ischemia. Methods/ Results: Combining an in vivo model of myocardial I/R, multimodal in vivo imaging approaches including Light-Sheet-Fluorescence-Microscopy, hybrid PET/MRI, speckle-tracking echocardiography and Next-generation deep sequencing analysis of platelet miRNA expression pattern in mice with a MK/platelet-specific knockout of pre-miRNA processing ribonuclease Dicer, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular process orchestrating left ventricular remodeling after myocardial I/R following transient LAD ligation. Global screening of the miRNA expression profile in murine platelets revealed a repertoire being comparable to human platelets in range and variety with a total number of 427 miRNAs attributing to 231 miRNA families, of which 81 miRNAs were significantly regulated in a Dicer-dependent manner. Disruption of miRNA processing machinery in platelets by deletion of Dicer resulted in an increased infarct size with elevated accumulation of platelet aggregates within the ischemic myocardial tissue, fostered myocardial inflammation, impaired border zone angiogenesis and accelerated long-term development of cardiac fibrosis. Deteriorated cardiac remodeling after myocardial infarction (MI) in mice with a platelet-specific Dicer deletion culminated in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at d28 post-MI altogether resulting in an exacerbated long-term cardiac recovery after experimental MI. Conclusion: This study is the first aiming to define the role of platelet-derived miRNAs for the pathophysiological process underlying myocardial I/R injury in vivo. The present study discloses a key role of platelet-derived miRNAs that are selectively regulated in response to myocardial I/R in a Dicer-dependent manner in influencing the myocardial healing process indicating their regulatory function in orchestrating the finely tuned cellular process underlying myocardial remodeling.

https://dgk.org/kongress_programme/jt2022/aP777.html