Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 94; no. 9; pp. 1005 - 1014
• Main Authors: Mühlstedt, Silke, Ghadge, Santhosh K., Duchene, Johan, Qadri, Fatimunnisa, Järve, Anne, Vilianovich, Larisa, Popova, Elena, Pohlmann, Andreas, Niendorf, Thoralf, Boyé, Philipp, Özcelik, Cemil, Bader, Michael
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2016; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Biopsy; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Disease Models, Animal; Fibrosis; Gene Expression; Human Genetics; Immunohistochemistry; Internal Medicine; Mice; Mice, Knockout; Molecular Medicine; Myocardial Infarction - diagnosis; Myocardial Infarction - etiology; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Organ Specificity - genetics; Organogenesis - genetics; Original Article; Prognosis; Rats; Rats, Transgenic; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - pathology; Myocardial infarction; Inflammation; CXCL12; Fibrosis; Hypertrophy
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-016-1432-1

The chemokine CXCL12/SDF-1 is crucial for heart development and affects cardiac repair processes due to its ability to attract leukocytes and stem cells to injured myocardium. However, there is a great controversy whether CXCL12 is beneficial or detrimental after myocardial infarction (MI). The divergence in the reported CXCL12 actions may be due to the cellular source and time of release of the chemokine after MI. This study was designed to evaluate the role of cardiomyocyte-derived CXCL12 for cardiogenesis and heart repair after MI. We generated two rodent models each targeting CXCL12 in only one cardiac cell type: cardiomyocyte-specific CXCL12-overexpressing transgenic (Tg) rats and CXCL12 conditional knockout (cKO) mice. Animals of both models did not show any signs of cardiac abnormalities under baseline conditions. After induction of MI, cKO mice displayed preserved cardiac function and remodeling. Moreover, fibrosis was less pronounced in the hearts of cKO mice after MI. Accordingly, CXCL12 Tg rats revealed impaired cardiac function post-MI accompanied by enhanced fibrosis. Furthermore, we observed decreased numbers of infiltrating T
h
1 cells in the hearts of cKO mice. Collectively, our findings demonstrate that cardiomyocyte-derived CXCL12 is not involved in cardiac development but has adverse effects on the heart after injury via promotion of inflammation and fibrosis.
Key messages
• CXCL12 in cardiomyocytes is not involved in cardiac development.
• CXCL12 deficiency in cardiomyocytes improves outcome of myocardial infarction.
• CXCL12 overexpression in cardiomyocytes worsens outcome of myocardial infarction.
• CXCL12 increases fibrosis and invasion of T
h
1 cells in the heart after infarction.