Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment.

Targeting the tumor microenvironment is critical toward improving the effectiveness of cancer therapeutics. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types of the tumor microenvironment, playing an important role in tumor progression. Multiple origins for CAFs have been proposed including resident fibroblasts, adipocytes, and bone marrow.

Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction.

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions.

Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice.

Rationale: Myocardial infarction (MI) causes an imbalance between matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases (TIMPs) and is associated with adverse left ventricular (LV) remodeling. A uniform reduction in TIMP-4 post-MI has been observed.

Objective: To examine post-MI remodeling with cardiac-restricted overexpression of TIMP-4, either through a transgenic or viral delivery approach.

Reproducible porcine model of thoracic aortic aneurysm.

Background: Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for the detection of TAA disease. This is largely driven by the lack of a large animal model, which would permit longitudinal/mechanistic studies.

Pulmonary artery endothelial cell phenotypic alterations in a large animal model of pulmonary arteriovenous malformations after the Glenn shunt.

Background: Longevity of the superior cavopulmonary connection (SCPC) is limited by the development of pulmonary arteriovenous malformations (PAVM). The goal of this study was to determine whether phenotypic changes in pulmonary artery endothelial cells (PAEC) that favor angiogenesis occur with PAVM formation.

Methods: A superior vena cava to right pulmonary artery connection was constructed in 5 pigs.

Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease.

Background: Thoracic aortic aneurysms (TAAs) develop through an asymptomatic process resulting in gross dilation that progresses to rupture if left undetected and untreated. If detected, patients with TAA are followed over time until the risk of rupture outweighs the risk of surgical repair. Current methodologies for tracking TAA size are limited to expensive computed tomography or magnetic resonance imaging because no acceptable population screening tools are currently available.

Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling.

The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP(+/-)), and wild type.

Continuous localized monitoring of plasmin activity identifies differential and regional effects of the serine protease inhibitor aprotinin: relevance to antifibrinolytic therapy.

Background: Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis after cardiac surgery. However, aprotinin was empirically dosed, and although the pharmacological target was the inhibition of plasmin activity (PLact), this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact.

Long-term localized high-frequency electric stimulation within the myocardial infarct: effects on matrix metalloproteinases and regional remodeling.

Background: Disruption of the balance between matrix metalloproteinases (MMP) and MMP inhibitors (TIMPs) within a myocardial infarct (MI) contributes to left ventricular wall thinning and changes in regional stiffness at the MI region. This study tested the hypothesis that a targeted regional approach through localized high-frequency stimulation (LHFS) using low-amplitude electric pulses instituted within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning.

Methods And Results: At 3 weeks after MI, pigs were randomized for LHFS (n=7; 240 bpm, 0.