Macrophages derived from septic mice modulate nitric oxide synthase and angiogenic mediators in the heart

Abstract

Macrophages (Mps) can exert the defense against invading pathogens. During sepsis, bacterial lipopolisaccharide (LPS) activates the production of inflammatory mediators by Mps. Nitric oxide synthase (NOS) derived-nitric oxide (NO) is one of them. Besides, Mps may produce pro-angiogenic molecules such as vascular endothelial growth factor-A (VEGF-A) and metalloproteinases (MMPs). The mechanisms involved in the cardiac neovascular response by Mps during sepsis are not completely known. We investigated the ability of LPS-treated Mps from septic mice to modulate the behavior of cardiac cells as producers of NO and angiogenic molecules. In vivo LPS treatment (0.1 mg/mouse) increased NO production more than fourfold and induced de novo NOS2 expression in Mps. Immunoblotting assays also showed an induction in VEGF-A and MMP-9 expression in lysates obtained from LPS-treated Mps, and MMP-9 activity was detected by zymography in cell supernatants. LPS-activated Mps co-cultured with normal heart induced the expression of CD31 and VEGF-A in heart homogenates and increased MMP-9 activity in the supernatants. By immunohistochemistry, we detected new blood vessel formation in hearts cultured with LPS treated Mps. When LPS-stimulated Mps were co-cultured with isolated cardiomyocytes in a transwell assay, the expression of NOS2, VEGF-A and MMP-9 was induced in cardiac cells. In addition, MMP-9 activity was up-regulated in the supernatant of cardiomyocytes. The latter was due to NOS2 induction in Mps from in vivo LPS-treated mice. In conclusion LPS-treated Mps are inducers of inflammatory/angiogenic mediators in cardiac cells, which could be triggering neovascularization, as an attempt to improve cardiac performance in sepsis.

Treatment with a New Peroxisome Proliferator-Activated Receptor Gamma Agonist, Pyridinecarboxylic Acid Derivative, Increases Angiogenesis and Reduces Inflammatory Mediators in the Heart of Trypanosoma cruzi-Infected Mice

“…Furthermore, Shrestha et al ( 50 ) demonstrated that T. cruzi infection increases the inflammatory and angiogenic mediators in the heart of infected mice ( 50 ). Taking into account that the evolution of Chagas disease is linked to microvascular lesions, including obstruction due to thrombosis, perivascular inflammation, and lesions in the coronary arterioles ( 33 ), we believe that the increased neovascularization observed during T. cruzi infection may act as a delaying factor of the physiopathological mechanisms leading to the cardiac symptoms during the course of Chagas disease.…”

“…Ashoff et al demonstrated that treatment of diabetic rats with pioglitazone, a synthetic PPARγ agonist, increases the density of capillaries in heart and skeletal muscle ( 51 ). Besides, de la Torre et al ( 33 ) demonstrated that LPS-treated macrophages from septic mice show increased CD31 and VEGF-A expression in the heart ( 33 ).…”

“…Macrophages (1.5 × 10 6 ) from uninfected, T. cruzi -infected and T. cruzi -infected HP 24 -treated mice were obtained and cultured with heart slices (100 mg/sample) from uninfected and T. cruzi -infected mice in 4 ml RPMI-1640 culture medium (Invitrogen Life Technologies, Grand Island, NY, USA). After 48 h, the culture supernatants were collected, and hearts were homogenized to obtain total proteins as previously described ( 33 ).…”

Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis after Major Abdominal Surgery

“…However, these biomarkers were not explored in surgical sepsis which is considered significantly different from sepsis in medical patients [ 16 ] or in major abdominal surgery per se. Also, aside from acute kidney injury (AKI) [ 17 ], the association of MMP-9 and TIMP-1 with the clinical manifestations of sepsis-associated organ dysfunction has not yet been investigated despite numerous animal models of sepsis that clearly demonstrate elevated expression of these biomarkers in the kidney [ 18 ], lung [ 18 – 21 ], liver [ 18 , 21 ], brain [ 22 ], heart [ 23 ], and endothelium [ 24 ].…”

Endogenous lysophosphatidic acid participates in vascularisation and decidualisation at the maternal–fetal interface in the rat

“…The coordination of vascular processes at the maternal-fetal interfase ensures an adequate blood flow in response to the increasing metabolic demands of the embryo (Torry et al 2007, Shimizu et al 2012. Blood vessels development is crucial during inflammation under pathological conditions like septic shock (de la Torre et al 2013), and in the physiological step of implantation (Demir et al 2010). This process involves the action of several growth factors, cytokines and chemokines (Blois et al 2011).…”