TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction.
ABSTRACT The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3(-/-)). The coronary artery was ligated in timp-3(-/-) and age-matched WT mice. At various time points over the following 28-day period, left ventricular structure and function (by echocardiography, pressure-volume measurements and morphometry), MMP levels and activity, blood vessel density, cell proliferation, apoptosis, matrix structure, and inflammatory cytokine levels were assessed in both groups. After ligation, mortality was significantly greater in timp-3(-/-) than in WT mice. Morphometry and echocardiography demonstrated no difference in heart size or function prior to ligation; however, the progression of left ventricular systolic dysfunction was accelerated in timp-3(-/-) mice at 7, 14 and 28 days after infarction compared to WT controls. Left ventricular dilatation, gelatinase MMP activity, and TNF-alpha levels were significantly greater in timp-3(-/-) than in WT mice at different times after ligation. By histological evaluation, timp-3(-/-) mice exhibited significantly increased blood vessel density, cell proliferation, and apoptosis in the infarct area, and reduced collagen content in the viable remote myocardium compared to WT mice at 7 and 14 days after ligation. TIMP-3 deficiency accelerated maladaptive cardiac remodeling after a myocardial infarction by promoting matrix degradation and inflammatory cytokine expression. This study supports further investigations to determine whether such remodeling could be reduced by augmenting TIMP-3 expression in the infarcted myocardium.
[show abstract] [hide abstract]
ABSTRACT: Unraveling the biological role of tissue inhibitors of metalloproteinases (TIMPs) during cardiac remodeling and the progression of heart failure has proven to be an enormous challenge. Remodeling of the cardiac extracellular matrix (ECM), regulated by matrix metalloproteinases (MMPs) and their endogenous inhibitors, TIMPs, is a well-established paradigm in cardiac health and disease. Originally, TIMPs were thought to function exclusively as endogenous inhibitors of MMP activity, thereby fine-tuning MMP-mediated ECM degradation and numerous related processes. However, during the last two decades, the concept of MMP-independent TIMP-mediated receptor signaling and regulation of cell fate has emerged. Although our current knowledge is still limited, in this review, we highlight some of the novel data, illustrating the MMP-independent biological properties of the four TIMP family members. Moreover, we discuss how these cell-specific insights may contribute to the process of cardiac remodeling, disease and failure. Finally, we identify where additional research is needed that will codetermine the possible future of TIMPs as therapeutic targets.Journal of Molecular and Cellular Cardiology 09/2009; 48(3):445-53. · 5.17 Impact Factor
Article: HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3.[show abstract] [hide abstract]
ABSTRACT: HMGB1 injection into the mouse heart, acutely after myocardial infarction (MI), improves left ventricular (LV) function and prevents remodeling. Here, we examined the effect of HMGB1 in chronically failing hearts. Adult C57 BL16 female mice underwent coronary artery ligation; three weeks later 200 ng HMGB1 or denatured HMGB1 (control) were injected in the peri-infarcted region of mouse failing hearts. Four weeks after treatment, both echocardiography and hemodynamics demonstrated a significant improvement in LV function in HMGB1-treated mice. Further, HMGB1-treated mice exhibited a ∼23% reduction in LV volume, a ∼48% increase in infarcted wall thickness and a ∼14% reduction in collagen deposition. HMGB1 induced cardiac regeneration and, within the infarcted region, it was found a ∼2-fold increase in c-kit⁺ cell number, a ∼13-fold increase in newly formed myocytes and a ∼2-fold increase in arteriole length density. HMGB1 also enhanced MMP2 and MMP9 activity and decreased TIMP-3 levels. Importantly, miR-206 expression 3 days after HMGB1 treatment was 4-5-fold higher than in control hearts and 20-25 fold higher that in sham operated hearts. HMGB1 ability to increase miR-206 was confirmed in vitro, in cardiac fibroblasts. TIMP3 was identified as a potential miR-206 target by TargetScan prediction analysis; further, in cultured cardiac fibroblasts, miR-206 gain- and loss-of-function studies and luciferase reporter assays showed that TIMP3 is a direct target of miR-206. HMGB1 injected into chronically failing hearts enhanced LV function and attenuated LV remodelling; these effects were associated with cardiac regeneration, increased collagenolytic activity, miR-206 overexpression and miR-206 -mediated inhibition of TIMP-3.PLoS ONE 01/2011; 6(6):e19845. · 4.09 Impact Factor