Background: Myocardial infarction (MI), a clinical manifestation of coronary artery disease (CAD), leads to accumulation of leukocytes in the ischemic myocardium. The initiation and progression of atherosclerotic plaques is driven by chronic vascular leukocyte recruitment as well. SVEP1 (Sushi, von Willebrand Factor Type A, Endothelin and Pentraxin domains- containing 1) is a highly conserved extracellular matrix (ECM) protein which is essential for vascular development and integrity. Previous work showed that variants in SVEP1 are associated with CAD and that SVEP1 mitigates vascular leukocyte recruitment to atherosclerotic plaques.
Objective: To characterize the functional and mechanistic effects of SVEP1 on leukocyte recruitment after acute myocardial infarction.
Methods and Results: As a full knockout of Svep1 is lethal, we generated haploinsufficuent Svep1+/- mice and performed ligation of the proximal left anterior descending artery to study the effects of Svep1-deficiency in myocardial infarction in vivo. Svep1+/+ mice were used as a control. Echocardiographic imaging revealed a reduced systolic left ventricular function (LV-EF) in Svep1+/- as compared to Svep1+/+ mice after 4 weeks. Flow cytometry analyses of left ventricle cell lysates revealed more enhanced leukocyte recruitment into the ischemic area of Svep1+/- mice after 72 hours which was also confirmed by adoptive transfer experiments. Cytokine profiling of human and murine samples indicated that these effects might be mediated by Angpt1 (Angiopoietin-1). Using co-immunoprecipitation, we found that SVEP1 and ANGPT1 directly interact with each other. On a functional level, ANGPT1 promoted adhesion of leukocytes to endothelial cells which was alleviated in the presence of SVEP1. Using enzyme-linked immunoadsorbent assays (ELISA), we observed a mitigation of ANGPT1-mediated intracellular signaling modulated by SVEP1.
Conclusion: We hypothesize that SVEP1 alleviates detrimental ventricular leukocyte recruitment after MI by modulating the effects of ANGPT1 on leukocyte recruitment. Increasing SVEP1 in the myocardium or inhibiting its degradation secondary to MI might be novel strategy to improve outcomes in MI patients.
