Cell Migration Inducing Protein (Cemip) deletion worsens cardiac outcome after cardiac ischemia/reperfusion in mice

Introduction: CEMIP (Cell Migration Inducing Protein) is an enzyme which is mainly expressed in fibroblasts. It is involved in hyaluronan (HA) depolymerization and can be found in different tissue types and organs such as the brain, the inner ear and the lymph nodes. Furthermore, CEMIP has been implicated in the unfolded protein response (UPR) following endoplasmic reticulum (ER)-stress.

Objectives: In previous work we have shown the critical role of HA in the fibroblast and macrophage response and thereby the healing after acute myocardial infarction (AMI) (Petz et al. Circ. Res. 2019). However, the effect of CEMIP on the postinfarction HA matrix and its function in AMI is unknown. In this project we aim to unveil CEMIPs function in the healing process of AMI using an ischemia/reperfusion (I/R) model.

Materials & methods: The course of Cemip expression in the left ventricle of C57BL/6J mice was analyzed after cardiac I/R. Furthermore, we analyzed CAGG-Cre-ERTM+/- Cemip fl/fl (Cemip-KO) versus CAGG-Cre-ERTM-/- Cemip fl/fl (control) mice after injection of tamoxifen to induce global Cemip deletion. Echocardiography was performed at baseline and after cardiac I/R, at 24h, 1 week, 2 weeks and 3 weeks. In addition, cardiac fibroblasts were isolated from murine hearts to study Cemip expression and function ex vivo. In order to identify regulators of Cemip, cardiac fibroblasts were treated with growth factors, as well as ER-stressors to examine CEMIPs gene expression, which was determined by qPCR.

Results: Cemip mRNA expression was significantly upregulated 72h post I/R (Cemip mRNA expression 19.99-fold of control, SD = 8.007, n = 8, p < 0.0001). As determined by echocardiography ejection fraction was significantly decreased and end diastolic and end systolic volume were significantly increased at 1 week, 2 weeks and 3 weeks post I/R in Cemip-KO mice compared to control mice. Moreover, the ER-stressor Thapsigargine (1µM) decreased Cemip mRNA expression significantly (Cemip mRNA expression 0.095-fold of control, SD = 0.023, n = 8, p < 0.0001).

Conclusion: According to our data CEMIP is a novel modifier in post myocardial infarction healing. Whether CEMIP affects healing by shaping the HA matrix and/or the fibroblast function warrants further investigation.