Anti-TIMP4 polyclonal antibody [Biotin]

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors ofmetalloproteinases (TIMPs) are involved in vascular and right ventricular remodeling in pulmonary hypertension (PH). MMP2, MMP9, TIMP1, and TIMP4 were measured in plasma and their potential as biomarkers for PH was evaluated. Methods: Consecutive patients undergoing right heart catheterization for suspected PH were included in this study (patients with mPAP >= 25 mm Hg were classed as having PH; those with mPAP <25 mm Hg served as non-PH controls). In total, 160 patientswith PH (idiopathic pulmonary arterial hypertension, pulmonary arterial hypertension associatedwith connective tissue disease, chronic thromboembolic PH, and pulmonary venous hypertension) and 44 non-PH controls were included. Plasma fromthe time of PH diagnosiswas analyzed for levels of MMP2, MMP9, TIMP1, and TIMP4 using enzyme immunoassays. Correlation analyses were performed with Pearson's or Spearman's coefficient, as appropriate. Mortality hazard ratios were derived using Cox regression analyses. Results: Plasma levels of MMP2, MMP9, TIMP1, and TIMP4 showed considerable overlap between patient groups. In patientswith PH, MMP2, TIMP1, and TIMP4 levels correlatedwith hemodynamic parameters (p < 0.05) and six minute walking distance (p < 0.01). Patients with high (>median) MMP2 and TIMP1 plasma levels had significantly worse 5-year survival than patients with low (<= median) plasma levels (multivariate mortality hazard ratios: 2.69 and 4.46, respectively; p < 0.01). Conclusions: MMP2 and TIMP1 plasma levels in patients with PH reflect disease severity and predict outcome. Though not being of diagnostic value, elevated biomarker plasma levels are strongly associated with increased risk in patients with PH. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

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. Methods and Results: MI was induced in mice and then randomized to targeted injection of an adenoviral construct (10 L; 8x10(9) plaque forming units/mL) encoding green fluorescent protein (GFP) and the full-length human TIMP-4 (Ad-GFP-TIMP4) or GFP. A transgenic construct with cardiac-restricted overexpression TIMP-4 (hTIMP-4exp) was used in a parallel set of studies. LV end-diastolic volume, an index of LV remodeling, increased by >60% from baseline at 5 days post-MI and by >100% at 21 days post-MI in the Ad-GFP only group. However, LV dilation was reduced by approximate to 50% in both the Ad-GFP-TIMP4 and hTIMP-4exp groups at these post-MI time points. LV ejection fraction was improved with either Ad-GFP-TIMP-4 or hTIMP-4exp. Fibrillar collagen expression and content were increased within the MI region with both TIMP-4 interventions, suggestive of matrix stabilization. Conclusions: This study is the first to demonstrate that selective myocardial targeting for TIMP-4 induction through either a viral or transgenic approach favorably altered the course of adverse LV remodeling post-MI. Thus, localized induction of endogenous matrix metalloproteinase inhibitors, such as TIMP-4, holds promise as a means to interrupt the progression of post-MI remodeling.