The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling.

Cardiac plasmin activity is increased following myocardial ischemia. To test the hypothesis that macrophage-derived uPA is a key mediator of repair following myocardial infarction, we performed myocardial infarction on mice with macrophage-specific over-expression of uPA (SR-uPA mice). SR-uPA(+/0) mice and wild-type littermates were sacrificed at 5 days or 4 weeks after infarction and cardiac content of macrophages, collagen, and myofibroblasts was quantified. Cardiac function and dimensions were assessed by echocardiography at baseline and at 4 weeks post-infarction. At 4 weeks after myocardial infarction, macrophage counts were increased in SR-uPA(+/0) mice in the infarct (13.1 vs. 4.9%, P<0.001) and distant uninfarcted regions (5.9 vs. 2.4%, P<0.001). Infarct scar was thicker in SR-uPA(+/0) mice (0.54+/-0.03 mm vs. 0.45+/-0.03 mm, P<0.05) and infarct cardiac collagen content was increased (72.4+/-3.3% vs. 63.0+/-3.6%, P<0.06). Functionally, these changes resulted in mildly improved fractional shortening in SR-uPA(+/0) mice compared to controls (24.6+/-1.68 vs. 19.8+/-1.3%, P=0.03). At 5 days after infarction there was increased collagen content in the scar without increases in macrophages or myofibroblasts. To understand the mechanisms by which macrophage-derived uPA increases collagen, cardiac fibroblasts were treated with macrophage-conditioned medium or plasmin and expression of ColIalpha1 measured by qPCR. Conditioned media from SR-uPA(+/0) or plasmin-treated non-transgenic macrophages but not plasmin alone increased collagen expression in isolated cardiac fibroblasts. We hypothesize that plasmin generation in the heart in response to injury may induce activation of macrophages to a profibrotic phenotype to allow rapid formation of collagenous scar.

Interest in a digital health tool in veterans with epilepsy: results of a phone survey.

OBJECTIVE: Online tools for managing chronic health conditions are becoming increasingly popular. Perceived benefits include ease of use, low costs, and availability but are contingent on patient engagement, Internet access, and digital literacy. This article describes data collected during the recruitment phase of a study evaluating an online self-management platform for epilepsy in a U.S. Veteran population. METHODS: We used administrative data to identify and contact Veterans with a likely diagnosis of epilepsy in the Veterans Health Administration (VHA). Veterans who did not respond directly to a mailed invitation were recruited by phone to determine study interest and evaluate digital access. RESULTS: Of the 2,143 Veterans mailed study invitations, phone calls were made to 1,789 who did not specifically decline participation. Among those reached by phone (n = 1,053): 295 (28%) expressed interest in the study and an online tool, 333 (19%) reported a lack of computer and/or Internet access and 425 (40%) were not interested for other reasons. CONCLUSIONS: This study suggests an interest in online tools for managing health despite the fact that some Veterans lack computer and/or Internet access. As investment in digital health solutions grows, the VHA should prioritize the widespread provision of digital access to more Veterans.

Urokinase plasminogen activator induces pro-fibrotic/m2 phenotype in murine cardiac macrophages.

OBJECTIVE: Inflammation and fibrosis are intertwined in multiple disease processes. We have previously found that over-expression of urokinase plasminogen activator in macrophages induces spontaneous macrophage accumulation and fibrosis specific to the heart in mice. Understanding the relationship between inflammation and fibrosis in the heart is critical to developing therapies for diverse myocardial diseases. Therefore, we sought to determine if uPA induces changes in macrophage function that promote cardiac collagen accumulation. METHODS AND RESULTS: We analyzed the effect of the uPA transgene on expression of pro-inflammatory (M1) and pro-fibrotic (M2) genes and proteins in hearts and isolated macrophages of uPA overexpressing mice. We found that although there was elevation of the pro-inflammatory cytokine IL-6 in hearts of transgenic mice, IL-6 is not a major effector of uPA induced cardiac fibrosis. However, uPA expressing bone marrow-derived macrophages are polarized to express M2 genes in response to IL-4 stimulation, and these M2 genes are upregulated in uPA expressing macrophages following migration to the heart. In addition, while uPA expressing macrophages express a transcriptional profile that is seen in tumor-associated macrophages, these macrophages promote collagen expression in cardiac but not embryonic fibroblasts. CONCLUSIONS: Urokinase plasminogen activator induces an M2/profibrotic phenotype in macrophages that is fully expressed after migration of macrophages into the heart. Understanding the mechanisms by which uPA modulates macrophage function may reveal insights into diverse pathologic processes.