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Zamaneh Kassiri - One of the best experts on this subject based on the ideXlab platform.
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biology of tissue inhibitor of metalloproteinase 3 timp3 and its therapeutic implications in cardiovascular pathology
Frontiers in Physiology, 2020Co-Authors: Dong Fan, Zamaneh KassiriAbstract:Tissue inhibitor of metalloproteinase 3 (TIMP3) is unique among the four TIMPs due to its extracellular matrix (ECM)-binding property and broad range of inhibitory substrates that includes matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs). In addition to its metalloproteinase-inhibitory function, TIMP3 can interact with proteins in the extracellular space resulting in its multifarious functions. TIMP3 mRNA has a long 3' untranslated region (UTR) which is a target for numerous microRNAs. TIMP3 levels are reduced in various cardiovascular diseases, and studies have shown that TIMP3 replenishment ameliorates the disease, suggesting a therapeutic potential for TIMP3 in cardiovascular diseases. While significant efforts have been made in identifying the effector targets of TIMP3, the regulatory mechanism for the expression of this multi-functional TIMP has been less explored. Here, we provide an overview of TIMP3 gene structure, transcriptional and post-transcriptional regulators (transcription factors and microRNAs), protein structure and partners, its role in cardiovascular pathology and its application as therapy, while also drawing reference from TIMP3 function in other diseases.
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timp3 deficiency exacerbates iron overload mediated cardiomyopathy and liver disease
American Journal of Physiology-heart and Circulatory Physiology, 2018Co-Authors: Pavel Zhabyeyev, Subhash K. Das, Zamaneh Kassiri, Ratnadeep Basu, Vaibhav B. Patel, Mengcheng Shen, Gavin Y. OuditAbstract:Chronic iron overload results in heart and liver diseases and is a common cause of morbidity and mortality in patients with genetic hemochromatosis and secondary iron overload. We investigated the role of tissue inhibitor of metalloproteinase 3 (TIMP3) in iron overload-mediated tissue injury by subjecting male mice lacking Timp3 ( Timp3-/-) and wild-type (WT) mice to 12 wk of chronic iron overload. Whereas WT mice with iron overload developed diastolic dysfunction, iron-overloaded Timp3-/- mice showed worsened cardiac dysfunction coupled with systolic dysfunction. In the heart, loss of Timp3 was associated with increased myocardial fibrosis, greater TIMP1, matrix metalloproteinase ( Mmp) 2, and Mmp9 expression, increased active MMP-2 levels, and gelatinase activity. Iron overload in Timp3-/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin. Loss of Timp3 enhanced the hepatic inflammatory response to iron overload, leading to greater neutrophil and macrophage infiltration and increased hepatic fibrosis. Expression of inflammation-related MMPs (MMP-12 and MMP-13) and inflammatory cytokines (IL-1β and monocyte chemoattractant protein-1) was elevated to a greater extent in iron-overloaded Timp3-/- livers. Gelatin zymography demonstrated equivalent increases in MMP-2 and MMP-9 levels in WT and Timp3-/- iron-overloaded livers. Loss of Timp3 enhanced the susceptibility to iron overload-mediated heart and liver injury, suggesting that Timp3 is a key protective molecule against iron-mediated pathology. NEW & NOTEWORTHY In mice, loss of tissue inhibitor of metalloproteinase 3 ( Timp3) was associated with systolic and diastolic dysfunctions, twofold higher hepatic iron accumulation (attributable to constituently lower levels of ferroportin), and increased hepatic inflammation. Loss of Timp3 enhanced the susceptibility to iron overload-mediated injury, suggesting that Timp3 plays a key protective role against iron-mediated pathology.
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Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction
Cardiovascular research, 2014Co-Authors: Dong Fan, Jiwon Lee, Xiuhua Wang, Gavin Y. Oudit, Abhijit Takawale, Ratnadeep Basu, Vaibhav B. Patel, Vijay Kandalam, Zamaneh KassiriAbstract:Aims Tissue inhibitor of metalloproteinases (TIMPs) can mediate myocardial remodelling, hypertrophy, and fibrosis in heart disease. We investigated the impact of TIMP2 vs. TIMP3 deficiency in angiotensin II (Ang II)-induced myocardial remodelling and cardiac dysfunction. Methods and results TIMP2−/−, TIMP3−/−, and wild-type (WT) mice received Ang II/saline (Alzet pump) for 2 weeks. Ang II infusion resulted in enhanced myocardial hypertrophy and lack of fibrosis in TIMP2−/−, and conversely, excess fibrosis without hypertrophy in TIMP3−/− mice. Echocardiographic imaging revealed preserved ejection fraction in all groups; however, exacerbated left ventricular (LV) diastolic dysfunction was detected in Ang II-infused TIMP2−/− and TIMP3−/− mice, despite the suppressed Ang II-induced hypertension in TIMP3−/− mice. Enhanced hypertrophy in TIMP2−/− mice impaired active relaxation, while excess fibrosis in TIMP3−/− mice increased LV passive stiffness. Adult WT cardiomyocytes, only when co-cultured with cardiac fibroblasts, exhibited Ang II-induced hypertrophy which was suppressed in TIMP3−/− cardiomyocytes. In vitro studies on adult cardiofibroblasts (quiescent and cyclically stretched), and in vivo analyses, revealed that the increased fibrosis in TIMP3−/−-Ang II hearts is due to post-translational stabilization and deposition of collagen by matricellular proteins [osteopontin and Secreted Protein Acidic and Rich in Cysteine (SPARC)], which correlated with increased inflammation, rather than increased de novo synthesis. Reduced cross-linking enzymes, LOX and PLOD1, could underlie suppressed collagen deposition in TIMP2−/−-Ang II hearts. Conclusion TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function. TIMP2−/− and TIMP3−/− mice provide a unique opportunity to study myocardial hypertrophy and fibrosis independently, and their impact on cardiac dysfunction.
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TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury
Kidney international, 2013Co-Authors: Zuocheng Wang, Konrad S. Famulski, Jiwon Lee, Subhash K. Das, Xiuhua Wang, Philip F. Halloran, Gavin Y. Oudit, Zamaneh KassiriAbstract:Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2, whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts, and solute carriers. Renal injury in TIMP3 −/− , but not in TIMP2 −/− , mice increased the expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β, and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3 −/− mice, which was completely blocked in the kidneys of TIMP2 −/− mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3 −/− and its reduction in TIMP2 −/− mice. The activities of tumor necrosis factor-α–converting enzyme, caspase-3, and mitogen-activated kinases were elevated in the kidneys of TIMP3 −/− mice but not TIMP2 −/− mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3 −/− mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury: TIMP3 protects from damage, whereas TIMP2 promotes injury through MMP2 activation.
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timp3 is the primary timp to regulate agonist induced vascular remodelling and hypertension
Cardiovascular Research, 2013Co-Authors: Ratnadeep Basu, Jiwon Lee, Xiuhua Wang, Dong Fan, Abhijit Takawale, Vijay Kandalam, Jude S Morton, Sandra T Davidge, Zamaneh KassiriAbstract:Aims Hypertension is accompanied by structural remodelling of vascular extracellular matrix (ECM). Tissue inhibitor of metalloproteinases (TIMPs) inhibits matrix metalloproteinases (MMPs) that degrade the matrix structural proteins. In response to a hypertensive stimulus, the balance between MMPs and TIMPs is altered. We examined the role of TIMPs in agonist-induced hypertension. Methods and results We subjected TIMP-knockout mice to angiotensin II (Ang II) infusion, and found that Ang-II-induced hypertension in TIMP1−/−, TIMP2−/−, and TIMP4−/− mice was comparable to wild-type (WT) mice, but significantly suppressed in TIMP3−/− mice. Ex vivo pressure myography analyses on carotid and mesenteric arteries revealed that Ang-II-infused TIMP3−/− arteries were more distensible with impaired elastic recoil compared with the WT group. The acute response to vasoconstriction and vasodilation was intact in TIMP3−/− mesenteric and carotid arteries. Mesenteric arteries from TIMP3−/−-Ang II mice exhibited a reduced media-to-lumen ratio, suppressed collagen and elastin levels, elevated elastase and gelatinase proteolytic activities compared with WT-Ang II. TIMP3−/−-Ang II carotid arteries also showed adverse structural remodelling. Treatment of mice with doxycycline, a matrix metalloproteinase inhibitor, improved matrix integrity in mesenteric and carotid arteries in TIMP3−/−-Ang II and differentially regulated elastin and collagen levels in WT-Ang II vs. TIMP3−/−-Ang II. Conclusion Our study demonstrates a critical role for TIMP3, among all TIMPs, is preserving arterial ECM in response to Ang II. It is critical to acknowledge that the suppressed Ang-II-induced hypertension in TIMP3−/− mice is not a protective mechanism but owing to adverse remodelling in arterial matrix.
Paul J R Barton - One of the best experts on this subject based on the ideXlab platform.
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a quantitative gene expression profile of matrix metalloproteinases mmps and their inhibitors timps in the myocardium of patients with deteriorating heart failure requiring left ventricular assist device support
Journal of Heart and Lung Transplantation, 2006Co-Authors: Leanne E Felkin, E J Birks, Robert S George, Sissie Wong, A Khaghani, Magdi H Yacoub, Paul J R BartonAbstract:Background Mechanisms underlying the rapid deterioration of heart failure patients who subsequently require left ventricular assist device (LVAD) support are poorly understood. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a key role in myocardial remodelling and heart failure. We hypothesized that MMP and TIMP expression would be altered in these patients. Methods Quantitative polymerase chain reaction was used to measure myocardial messenger RNA levels of MMP1 to MMP14, TIMP1 to TIMP4, collagen I and collagen III in 24 dilated cardiomyopathy (DCM) patients with deteriorating clinical status who required LVAD support (LVAD Group) and in 7 stable DCM patients undergoing transplantation without need for LVAD support (Tx Group). Results Levels of MMP1, MMP8 and TIMP4 were higher in the LVAD Group compared with the Tx Group (188% ± 141%, 646% ± 432%, and 66% ± 33% higher, respectively, p Conclusions The data show that high myocardial collagenase (MMP1 and MMP8) expression without compensatory changes in collagen or TIMP expression is a feature of patients requiring LVAD support. This may be linked in part to elevated cytokine expression and suggests collagenase activity may be an important therapeutic target in deteriorating heart failure.
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increased expression of extracellular matrix regulators TIMP1 and mmp1 in deteriorating heart failure
Journal of Heart and Lung Transplantation, 2003Co-Authors: Leanne E Felkin, E J Birks, Paul J R Barton, Martin E Cullen, Maren U KobanAbstract:Abstract Background: The authors previously identified and compared alterations in gene expression in the myocardia of patients with deteriorating heart failure who underwent left ventricular assist device (LVAD) implantation with those of patients with stable end-stage failure (ESF). We hypothesized that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), would be implicated in the mechanisms that underlie deteriorating heart failure. Methods: Gridded macro-array filters were used to provide a broad overview of MMP and TIMP mRNA expression in heart failure. Precise mRNA levels of TIMP1, MMP1, and β-spectrin were determined using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) of myocardial samples from 27 patients with deteriorating heart failure who underwent LVAD implantation, from 17 patients with stable ESF who underwent elective heart transplantation, and from 28 donor organs with good hemodynamic function. Results: Gridded macro-arrays analysis of pooled failing heart samples determined that TIMP1 mRNA was the most readily detectable TIMP in failing myocardium. Quantitative RT-PCR showed that expression levels in individual patients were similar in patients with stable ESF (1.00 ± 0.24, n = 17) and in donor organ samples (1.49 ± 0.22, n = 28) but were significantly increased in the deteriorating heart failure group (5.38 ± 0.32, n = 26, p n = 27, p Conclusions: Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-β.
Maren U Koban - One of the best experts on this subject based on the ideXlab platform.
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increased expression of extracellular matrix regulators TIMP1 and mmp1 in deteriorating heart failure
Journal of Heart and Lung Transplantation, 2003Co-Authors: Leanne E Felkin, E J Birks, Paul J R Barton, Martin E Cullen, Maren U KobanAbstract:Abstract Background: The authors previously identified and compared alterations in gene expression in the myocardia of patients with deteriorating heart failure who underwent left ventricular assist device (LVAD) implantation with those of patients with stable end-stage failure (ESF). We hypothesized that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), would be implicated in the mechanisms that underlie deteriorating heart failure. Methods: Gridded macro-array filters were used to provide a broad overview of MMP and TIMP mRNA expression in heart failure. Precise mRNA levels of TIMP1, MMP1, and β-spectrin were determined using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) of myocardial samples from 27 patients with deteriorating heart failure who underwent LVAD implantation, from 17 patients with stable ESF who underwent elective heart transplantation, and from 28 donor organs with good hemodynamic function. Results: Gridded macro-arrays analysis of pooled failing heart samples determined that TIMP1 mRNA was the most readily detectable TIMP in failing myocardium. Quantitative RT-PCR showed that expression levels in individual patients were similar in patients with stable ESF (1.00 ± 0.24, n = 17) and in donor organ samples (1.49 ± 0.22, n = 28) but were significantly increased in the deteriorating heart failure group (5.38 ± 0.32, n = 26, p n = 27, p Conclusions: Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-β.
Leanne E Felkin - One of the best experts on this subject based on the ideXlab platform.
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a quantitative gene expression profile of matrix metalloproteinases mmps and their inhibitors timps in the myocardium of patients with deteriorating heart failure requiring left ventricular assist device support
Journal of Heart and Lung Transplantation, 2006Co-Authors: Leanne E Felkin, E J Birks, Robert S George, Sissie Wong, A Khaghani, Magdi H Yacoub, Paul J R BartonAbstract:Background Mechanisms underlying the rapid deterioration of heart failure patients who subsequently require left ventricular assist device (LVAD) support are poorly understood. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a key role in myocardial remodelling and heart failure. We hypothesized that MMP and TIMP expression would be altered in these patients. Methods Quantitative polymerase chain reaction was used to measure myocardial messenger RNA levels of MMP1 to MMP14, TIMP1 to TIMP4, collagen I and collagen III in 24 dilated cardiomyopathy (DCM) patients with deteriorating clinical status who required LVAD support (LVAD Group) and in 7 stable DCM patients undergoing transplantation without need for LVAD support (Tx Group). Results Levels of MMP1, MMP8 and TIMP4 were higher in the LVAD Group compared with the Tx Group (188% ± 141%, 646% ± 432%, and 66% ± 33% higher, respectively, p Conclusions The data show that high myocardial collagenase (MMP1 and MMP8) expression without compensatory changes in collagen or TIMP expression is a feature of patients requiring LVAD support. This may be linked in part to elevated cytokine expression and suggests collagenase activity may be an important therapeutic target in deteriorating heart failure.
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increased expression of extracellular matrix regulators TIMP1 and mmp1 in deteriorating heart failure
Journal of Heart and Lung Transplantation, 2003Co-Authors: Leanne E Felkin, E J Birks, Paul J R Barton, Martin E Cullen, Maren U KobanAbstract:Abstract Background: The authors previously identified and compared alterations in gene expression in the myocardia of patients with deteriorating heart failure who underwent left ventricular assist device (LVAD) implantation with those of patients with stable end-stage failure (ESF). We hypothesized that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), would be implicated in the mechanisms that underlie deteriorating heart failure. Methods: Gridded macro-array filters were used to provide a broad overview of MMP and TIMP mRNA expression in heart failure. Precise mRNA levels of TIMP1, MMP1, and β-spectrin were determined using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) of myocardial samples from 27 patients with deteriorating heart failure who underwent LVAD implantation, from 17 patients with stable ESF who underwent elective heart transplantation, and from 28 donor organs with good hemodynamic function. Results: Gridded macro-arrays analysis of pooled failing heart samples determined that TIMP1 mRNA was the most readily detectable TIMP in failing myocardium. Quantitative RT-PCR showed that expression levels in individual patients were similar in patients with stable ESF (1.00 ± 0.24, n = 17) and in donor organ samples (1.49 ± 0.22, n = 28) but were significantly increased in the deteriorating heart failure group (5.38 ± 0.32, n = 26, p n = 27, p Conclusions: Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-β.
Gavin Y. Oudit - One of the best experts on this subject based on the ideXlab platform.
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timp3 deficiency exacerbates iron overload mediated cardiomyopathy and liver disease
American Journal of Physiology-heart and Circulatory Physiology, 2018Co-Authors: Pavel Zhabyeyev, Subhash K. Das, Zamaneh Kassiri, Ratnadeep Basu, Vaibhav B. Patel, Mengcheng Shen, Gavin Y. OuditAbstract:Chronic iron overload results in heart and liver diseases and is a common cause of morbidity and mortality in patients with genetic hemochromatosis and secondary iron overload. We investigated the role of tissue inhibitor of metalloproteinase 3 (TIMP3) in iron overload-mediated tissue injury by subjecting male mice lacking Timp3 ( Timp3-/-) and wild-type (WT) mice to 12 wk of chronic iron overload. Whereas WT mice with iron overload developed diastolic dysfunction, iron-overloaded Timp3-/- mice showed worsened cardiac dysfunction coupled with systolic dysfunction. In the heart, loss of Timp3 was associated with increased myocardial fibrosis, greater TIMP1, matrix metalloproteinase ( Mmp) 2, and Mmp9 expression, increased active MMP-2 levels, and gelatinase activity. Iron overload in Timp3-/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin. Loss of Timp3 enhanced the hepatic inflammatory response to iron overload, leading to greater neutrophil and macrophage infiltration and increased hepatic fibrosis. Expression of inflammation-related MMPs (MMP-12 and MMP-13) and inflammatory cytokines (IL-1β and monocyte chemoattractant protein-1) was elevated to a greater extent in iron-overloaded Timp3-/- livers. Gelatin zymography demonstrated equivalent increases in MMP-2 and MMP-9 levels in WT and Timp3-/- iron-overloaded livers. Loss of Timp3 enhanced the susceptibility to iron overload-mediated heart and liver injury, suggesting that Timp3 is a key protective molecule against iron-mediated pathology. NEW & NOTEWORTHY In mice, loss of tissue inhibitor of metalloproteinase 3 ( Timp3) was associated with systolic and diastolic dysfunctions, twofold higher hepatic iron accumulation (attributable to constituently lower levels of ferroportin), and increased hepatic inflammation. Loss of Timp3 enhanced the susceptibility to iron overload-mediated injury, suggesting that Timp3 plays a key protective role against iron-mediated pathology.
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Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction
Cardiovascular research, 2014Co-Authors: Dong Fan, Jiwon Lee, Xiuhua Wang, Gavin Y. Oudit, Abhijit Takawale, Ratnadeep Basu, Vaibhav B. Patel, Vijay Kandalam, Zamaneh KassiriAbstract:Aims Tissue inhibitor of metalloproteinases (TIMPs) can mediate myocardial remodelling, hypertrophy, and fibrosis in heart disease. We investigated the impact of TIMP2 vs. TIMP3 deficiency in angiotensin II (Ang II)-induced myocardial remodelling and cardiac dysfunction. Methods and results TIMP2−/−, TIMP3−/−, and wild-type (WT) mice received Ang II/saline (Alzet pump) for 2 weeks. Ang II infusion resulted in enhanced myocardial hypertrophy and lack of fibrosis in TIMP2−/−, and conversely, excess fibrosis without hypertrophy in TIMP3−/− mice. Echocardiographic imaging revealed preserved ejection fraction in all groups; however, exacerbated left ventricular (LV) diastolic dysfunction was detected in Ang II-infused TIMP2−/− and TIMP3−/− mice, despite the suppressed Ang II-induced hypertension in TIMP3−/− mice. Enhanced hypertrophy in TIMP2−/− mice impaired active relaxation, while excess fibrosis in TIMP3−/− mice increased LV passive stiffness. Adult WT cardiomyocytes, only when co-cultured with cardiac fibroblasts, exhibited Ang II-induced hypertrophy which was suppressed in TIMP3−/− cardiomyocytes. In vitro studies on adult cardiofibroblasts (quiescent and cyclically stretched), and in vivo analyses, revealed that the increased fibrosis in TIMP3−/−-Ang II hearts is due to post-translational stabilization and deposition of collagen by matricellular proteins [osteopontin and Secreted Protein Acidic and Rich in Cysteine (SPARC)], which correlated with increased inflammation, rather than increased de novo synthesis. Reduced cross-linking enzymes, LOX and PLOD1, could underlie suppressed collagen deposition in TIMP2−/−-Ang II hearts. Conclusion TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function. TIMP2−/− and TIMP3−/− mice provide a unique opportunity to study myocardial hypertrophy and fibrosis independently, and their impact on cardiac dysfunction.
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TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury
Kidney international, 2013Co-Authors: Zuocheng Wang, Konrad S. Famulski, Jiwon Lee, Subhash K. Das, Xiuhua Wang, Philip F. Halloran, Gavin Y. Oudit, Zamaneh KassiriAbstract:Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2, whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts, and solute carriers. Renal injury in TIMP3 −/− , but not in TIMP2 −/− , mice increased the expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β, and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3 −/− mice, which was completely blocked in the kidneys of TIMP2 −/− mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3 −/− and its reduction in TIMP2 −/− mice. The activities of tumor necrosis factor-α–converting enzyme, caspase-3, and mitogen-activated kinases were elevated in the kidneys of TIMP3 −/− mice but not TIMP2 −/− mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3 −/− mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury: TIMP3 protects from damage, whereas TIMP2 promotes injury through MMP2 activation.
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loss of timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin ii
Journal of Biological Chemistry, 2012Co-Authors: Ratnadeep Basu, Jiwon Lee, Subhash K. Das, Xiuhua Wang, Gavin Y. Oudit, Dong Fan, Vijay Kandalam, Troy A Baldwin, Zamaneh KassiriAbstract:Aortic aneurysm is dilation of the aorta primarily due to degradation of the aortic wall extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the proteases that degrade the ECM. Timp3 is the only ECM-bound Timp, and its levels are altered in the aorta from patients with abdominal aortic aneurysm (AAA). We investigated the causal role of Timp3 in AAA formation. Infusion of angiotensin II (Ang II) using micro-osmotic (Alzet) pumps in Timp3−/− male mice, but not in wild type control mice, led to adverse remodeling of the abdominal aorta, reduced collagen and elastin proteins but not mRNA, and elevated proteolytic activities, suggesting excess protein degradation within 2 weeks that led to formation of AAA by 4 weeks. Intriguingly, despite early up-regulation of MMP2 in Timp3−/−Ang II aortas, additional deletion of Mmp2 in these mice (Timp3−/−/Mmp2−/−) resulted in exacerbated AAA, compromised survival due to aortic rupture, and inflammation in the abdominal aorta. Reconstitution of WT bone marrow in Timp3−/−/Mmp2−/− mice reduced inflammation and prevented AAA in these animals following Ang II infusion. Treatment with a broad spectrum MMP inhibitor (PD166793) prevented the Ang II-induced AAA in Timp3−/− and Timp3−/−/Mmp2−/− mice. Our study demonstrates that the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and AAA. Hence, replenishing TIMP3, a physiological inhibitor of a number of metalloproteinases, could serve as a therapeutic approach in limiting AAA development or expansion.
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early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking timp3 following myocardial infarction
American Journal of Physiology-heart and Circulatory Physiology, 2010Co-Authors: Vijay Kandalam, Xiuhua Wang, Gavin Y. Oudit, Ratnadeep Basu, Thomas Abraham, Ahmed Awad, Nobuyo Maeda, Wei Wang, Gary D Lopaschuk, Zamaneh KassiriAbstract:Extracellular matrix (ECM) remodeling is a critical aspect of cardiac remodeling following myocardial infarction. Tissue inhibitors of metalloproteinases (TIMPs) are physiological inhibitors of matrix metalloproteinases (MMPs) that degrade the ECM proteins. TIMP3 is highly expressed in the heart, and is markedly downregulated in patients with ischemic cardiomyopathy. We therefore examined the time- and region-dependent role of TIMP3 in the cardiac response to myocardial infarction (MI). TIMP3−/− and wild-type (WT) mice were subjected to MI by ligation of the left anterior descending artery. TIMP3−/−-MI mice exhibited a significantly compromised rate of survival compared with WT-MI mice, primarily due to increased left ventricular (LV) rupture, greater infarct expansion, exacerbated LV dilation, and greater systolic and diastolic dysfunction. Second harmonic generation imaging of unfixed and unstained hearts revealed greater collagen disarray and reduced density in the TIMP3−/− infarct myocardium compared with the WT group. Gelatinolytic and collagenolytic activities increased in TIMP3−/− compared with WT hearts at 1 day post-MI but not at 3 days or 1 wk post-MI. Neutrophil infiltration and inflammatory MMPs were significantly increased in the infarct and peri-infarct regions of TIMP3−/−-MI hearts. Treatment of TIMP3−/− mice with a broad-spectrum MMP inhibitor (PD-166793) for 2 days before and 2 days after MI markedly improved post-MI infarct expansion, LV rupture incident, LV dilation, and systolic dysfunction in these mice up to 1 wk post-MI. Our data demonstrate that the initial rise in proteolytic activities early post-MI is a triggering factor for subsequent LV adverse remodeling, LV rupture, and dilated cardiomyopathy. Hence, timing of treatments to improve cardiac response to MI may be critical in producing favorable outcome.
