Effects of Gene Deletion of the Tissue Inhibitor of the Matrix Metalloproteinase-type 1 (TIMP-1) on Left Ventricular Geometry and Function in Mice

Roten, Lisa; Nemoto, Shintaro; Simsic, Janet M.; Coker, Mytsi L.; Rao, Vijay U.; Baicu, Simona; DeFreyte, Gilberto; Soloway, Paul D.; Zile, Michael R.; Spinale, Francis G.

doi:10.1006/jmcc.1999.1052

Cited by 114 publications

(79 citation statements)

References 38 publications

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“…It was demonstrated that the expression of TIMP-1 and TIMP-2 increased significantly in chronic pressure-overloaded human hearts (Heymans et al, 2005b). When TIMP-1 was knocked out, mice suffered spontaneous LV dilatation, thus indicating the importance of the control of cardiac MMP activity by TIMP-1 (Roten et al, 2000). In the present study, we found that PC-Tg significantly suppressed the Ang II-induced cardiac remodeling, as revealed by the cardiomyocyte crosssectional area and cardiac fibrosis.…”

Section: Discussionsupporting

confidence: 61%

Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice

Pei

Yan

Tang

et al. 2016

Sci. China Life Sci.

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Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase (PON) gene cluster (PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene (PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type (WT) control. The same protective tendency was also observed with an Apoe / background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.cardiac hypertrophy, fibrosis, paraoxonase gene cluster, angiotensin II Citation:

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Section: Discussionsupporting

confidence: 61%

Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice

Pei

Yan

Tang

et al. 2016

Sci. China Life Sci.

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“…4,5 TIMP-1-deficient mice exhibit significant LV remodeling, suggesting that constitutive control of myocardial MMP activity is important in maintaining a normal LV phenotype. 21 The present study did not evaluate TIMP levels in the myocardium from HF rodents and how these levels might have been altered with long-term MMP inhibition. TIMP expression is a physiologically relevant counterbalance, modulating MMP activity in LV remodeling, which warrants further study.…”

Section: Myocardial Mmps and Myocardial Structurementioning

confidence: 93%

Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure

Peterson

Hallak²,

Johnson³

et al. 2001

Circulation

277

198

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Background-Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. Methods and Results-LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (nϭ10), (2) SHHF at 13 months (nϭ12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 PO; nϭ14), (4) normotensive Wistar-Furth rats (WF) at 9 months (nϭ12), and (5) WF at 13 months (nϭ12). Plasma concentrations of the MMP inhibitor (116Ϯ11 mol/L) reduced in vitro LV myocardial MMP-2 activity by Ϸ100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak ϩdP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578Ϯ477 versus 5983Ϯ109 mm Hg/s, PՅ0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443Ϯ12 versus 563Ϯ33 mL, PՅ0.05) and increased further by 13 months (899Ϯ64 mL, PՅ0.05). LV myocardial MMP-2 activity was increased by Ϸ2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak ϩdP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678Ϯ28 mL, PՅ0.05). Conclusions-MMP

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“…Loss of TIMP4 leads to enhanced MMP activity in the heart after ischemia, 16 and gene knockout of TIMP-1 exacerbates ventricular remodeling. 17 Pharmacological blockade of MMP activity leads to decreased ventricular remodeling. 18 -21 Noninvasive methodology to optically image MMP activity would be of use to follow the temporal and spatial patterns of MMP activity after MI and in assessing treatment approaches.…”

Section: See P 1730mentioning

confidence: 99%

Near-Infrared Fluorescent Imaging of Matrix Metalloproteinase Activity After Myocardial Infarction

et al. 2005

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Background-We used a molecular probe activated by protease cleavage to image expression of matrix metalloproteinases (MMPs) in the heart after myocardial infarction. Methods and Results-We synthesized and characterized a near-infrared fluorescent (NIRF) probe that is activated by proteolytic cleavage by MMP2 and MMP9. The NIRF probe was injected into mice at various time points up to 4 weeks after myocardial infarction induced by ligation of the left anterior descending coronary artery. NIRF imaging of MMP activity increased in the infarct region, with maximal expression at 1 to 2 weeks, persisting to 4 weeks. Zymography and real-time polymerase chain reaction analysis showed that MMP9 expression is increased at 2 to 4 days, and MMP2 expression is increased at 1 to 2 weeks. Dual-label confocal microscopy showed colocalization of NIRF imaging with neutrophils on day 2, and flow cytometric analysis confirmed that NIRF signal is associated with leukocytes in the infarct zone. Conclusions-This study demonstrates that the activity of MMPs in the myocardium may be imaged by use of specific activity-dependent molecular probes. (Circulation. 2005;111:1800-1805.)

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Effects of Gene Deletion of the Tissue Inhibitor of the Matrix Metalloproteinase-type 1 (TIMP-1) on Left Ventricular Geometry and Function in Mice

Cited by 114 publications

References 38 publications

Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice

Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice

Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure

Near-Infrared Fluorescent Imaging of Matrix Metalloproteinase Activity After Myocardial Infarction

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