Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice

Ovechkin, Alexander V.; Tyagi, Neetu; Rodríguez, Walter; Hayden, Melvin R.; Moshal, Karni S.; Tyagi, Suresh C.

doi:10.1152/japplphysiol.00442.2005

Cited by 46 publications

(32 citation statements)

References 30 publications

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“…Others and we previously suggested (12,19) a role of MMP activation and E-M uncoupling in cardiac remodeling and dysfunction in chronic heart failure. The results of this study showed that impaired arterial function in the HHcy model of arterial hy- Recently we demonstrated (20) that Hcy instigates a "negative vascular remodeling" or inward directed increase in arterial wall thickness and hypertension.…”

Section: Discussionmentioning

confidence: 73%

“…Twenty-five micrograms of total protein from aortic homogenates was loaded in each well, run on 10% SDS-PAGE, and transferred to polyvinylidene difluoride membranes. The membranes were blotted with anti-connexin 43 monoclonal antibodies (Chemicon) as previously described (19). Secondary IgG-alkaline phosphatase was used for detection.…”

Section: Methodsmentioning

confidence: 99%

“…Cardiovascular remodeling is associated with accumulation of ECM components between endothelial and muscle cells (16,17) and is one of the most important factors of endothelial dysfunction (11,14). Degradation of interstitial collagen and elastin by MMPs leads to increased ECM formation and endotheliummuscle uncoupling (17,19), because the more collagen is degraded, the more of it is synthesized (28). There are more than 20 MMPs in the family, but increase in MMP-2 and -9 activities has a more pronounced effect during early and late phases of cardiovascular remodeling (27).…”

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confidence: 99%

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3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

Ovechkin¹,

Tyagi²,

Sen³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic hyperhomocysteinemia (HHcy) is an important factor in development of arterial hypertension. HHcy is associated with activation of matrix metalloproteinases (MMPs); however, it is unclear whether HHcy-dependent extracellular matrix (ECM) accumulation plays a role in arterial hypertrophy and hypertension. We tested the hypothesis that in HHcy the mechanism of arterial hypertension involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and subsequent endothelium-myocyte (E-M) uncoupling. To decrease plasma Hcy, dietary supplementation with 3-deazaadenosine (DZA), the S-adenosylhomocysteine hydrolase inhibitor, was administered to cystathionine ␤-synthase (CBS) knockout (KO) mice. Mice were grouped as follows: wild type (WT; control), WTϩDZA, CBSKO, and CBSKOϩDZA (n ϭ 4/group). Mean aortic blood pressure and heart rate were monitored in real time with a telemetric system before, during, and after DZA treatment (6 wk total). In vivo aorta function and morphology were analyzed by M-mode and Doppler echocardiography in anesthetized mice. Aorta MMP activity in unfixed cryostat sections was measured with DQ gelatin. Aorta MMP-2, MMP-9, and connexin 43 expression were measured by RT-PCR and Western blot analyses, respectively. HHcy caused increased aortic blood pressure and resistance, tachycardia, and increased wall thickness and ECM accumulation in aortic wall vs. control groups. There was a linear correlation between aortic wall thickness and plasma Hcy levels. MMP-2, MMP-9, and connexin 43 expression were increased in HHcy. In the CBSKOϩDZA group, aortic blood pressure and levels of MMP and connexin 43 were close to those found in control groups. However, removal of DZA reversed the aortic lumen-to-wall thickness ratio in CBSKO mice, suggesting, in part, a role of vascular remodeling in the increase in blood pressure in HHcy. The results show that arterial hypertension in HHcy mice is, in part, associated with arterial remodeling and E-M uncoupling in response to MMP activation. cardiovascular dysfunction; aorta; echocardiography; extracellular matrix remodeling; in situ matrix metalloproteinase activity; cystathionine ␤-synthase; connexin; DQ gelatin; telemetry EXPERIMENTAL AND CLINICAL studies have shown that chronic elevation of homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), is a significant independent risk factor for cardiovascular disease (31), particularly in the development of arterial hypertension and atherosclerosis (3,24,26). The mechanisms by which HHcy affects arterial wall and induces arterial hypertension have remained unclear. It has been shown that HHcy leads to arterial damage (4) and increased arterial wall stiffness (2,22).Hcy is a product of methionine metabolism that under normal conditions is converted to cystathionine by cystathionine ␤-synthase (CBS). It has been established that mice carrying a disrupted CBS gene are adequate models for HHcy. Systemic vascular cells lacking CBS (7,8) are the prime target for...

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Section: Discussionmentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

Ovechkin¹,

Tyagi²,

Sen³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…From this, we inferred that H 2 S was indulged in mitigating proteolytic effect of MMPs caused by oxidative stress. ADAM-12 was a signal molecule downstream to proteinase-activated receptor-1 (PAR-1) that was involved in matrix remodeling (16). In AVF mice, ADAM-12 level increased but normalized after H 2 S treatment (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…TdT-mediated dUTP nick end labeling (TUNEL) assay was used to determine the number of apoptotic cells in the LV of 0 and 6 wk of AVF mice and 8 and 10 wk of H 2S-treated mice. LV tissues were snap-frozen following the procedure of Ovechkin et al (16) and labeled with TUNEL (Upstate Cell Signaling Solution, Lake Placid, NY) as per the instructions of the company. Cells were counted and scored from five randomly selected areas of each slide, and quantitative analysis was performed by employing Image-Pro Plus (Media Cybernetics, Silver Spring, MD).…”

Section: Methodsmentioning

confidence: 99%

H₂S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure

Mishra

Tyagi

Sen

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Mishra PK, Tyagi N, Sen U, Givvimani S, Tyagi SC. H2S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure. Am J Physiol Heart Circ Physiol 298: H451-H456, 2010. First published November 20, 2009; doi:10.1152/ajpheart.00682.2009.-Reactive oxygen and nitrogen species (ROS and RNS, respectively) generate nitrotyrosine and activate latent resident myocardial matrix metalloproteinases (MMPs). Although in chronic heart failure (CHF) there is robust increase in ROS, RNS, and MMP activation, recent data suggest that hydrogen sulfide (H 2S, a strong antioxidant gas) is cardioprotective. However, the role of H 2S in mitigating oxidative and proteolytic stresses in cardiac remodeling/apoptosis in CHF was unclear. To test the hypothesis that H 2S ameliorated cardiac apoptosis and fibrosis by decreasing oxidative and proteolytic stresses, arteriovenous fistula (AVF) was created in wild-type (C57BL/6J) mice. The hearts were analyzed at 0, 2, and 6 wk after AVF. To reverse the remodeling, AVF mice were treated with NaHS (an H 2S donor, 30 mol/l in drinking water) at 8 and 10 wk. The levels of MMPs were measured by gelatin-gel zymography. The levels of nitrotyrosine, tissue inhibitors of metalloproteinase (TIMPs), ␤ 1-integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were analyzed by Western blots. The levels of pericapillary and interstitial fibrosis were identified by Masson trichrome stains. The levels of apoptosis were measured by identifying the TdT-mediated dUTP nick end labeling (TUNEL)-positive cells and caspase-3 levels. The results suggested robust nitrotyrosine and MMP activation at 2 and 6 wk of AVF. The treatment with H 2S donor mitigated nitrotyrosine generation and MMP activation (i.e., oxidative and proteolytic stresses). The levels of TIMP-1 and TIMP-3 were increased and TIMP-4 decreased in AVF hearts. The treatment with H 2S donor reversed this change in TIMPs levels. The levels of ADAM-12, apoptosis, and fibrosis were robust and integrin were decreased in AVF hearts. The treatment with H 2S donor attenuated the fibrosis, apoptosis, and decrease in integrin. fibrosis; extracellular matrix; ADAM; integrin; matrix metalloproteinase; tissue inhibitor of metalloproteinase; left ventricle hypertrophy; collagen; TUNEL; apoptosis; homocysteine ALTHOUGH IN GASTROINTESTINAL and nervous systems hydrogen sulfide (H 2 S) plays a crucial role as a signaling molecule (12, 24), recent studies established that H 2 S is a cardioprotective gas (4, 21, 27). However, its role in regulating the ECM remodeling and apoptosis is still nebulous. Considering the tremendous therapeutic potential, H 2 S gas has attracted the attention of biomedical research (2,5,9,10,12). It is a strong antioxidant and is generated endogenously by two important enzymes involved in sulfur-containing amino acid [cysteine and homocysteine (Hcy)] metabolism, namely cystathionine ␤-synthase (CBS) and cystathionine ␥-lyase (CGL) (26). Paradoxically, it is interesting that hyperh...

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Signal Transduction in the Cardiovascular System in Health and Disease

Srivastava¹,

Anand‐Srivastava²

2008

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except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Cover illustration:Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com PrefaceIn recent years, there has been a surge of interest in studies related to the role of a variety of signaling pathways in the control of cardiovascular physiology. Evidence has also accumulated to suggest that an aberration in the signal transduction pathways contributes to the pathophysiology of cardiovascular disease. Several components of the signaling pathways have been identified as potential targets for the development of new therapies of cardiovascular disease. Therefore, this volume has been compiled to highlight the contributions of different signaling systems in modulating normal cardiovascular functions and how a perturbation in these signaling events leads to abnormal cell functions and cardiovascular disorders. This volume has been divided into five sections dealing with five key signaling pathways regulating different aspects of cardiovascular physiology. The first section describes the role of G-protein-coupled receptor (GPCR) signaling in cardiovascular functions. In this section, Anand-Srivastava has elegantly summarized studies showing that the expression levels of various G-proteins as well as responsiveness of adenylyl cyclase systems to various stimuli such as β-adrenergic receptor (βAR) agonist and vasoactive peptides are defective in various models of hypertension, congestive heart failure (CHF), cardiac hypertrophy, and other diseases. Dent et al. have highlighted studies showing how the alterations in different components of the βAR signaling system contribute to CHF and suggest that βAR blockade could be used as a strategy to treat CHF. Continuing on the same theme, Vacek et al. have reviewed the pathophysiological mechanisms involved in CHF and sudden cardiac death, with an emphasis on the role of homocysteine-induced cross talk between NMDA receptor and GPCRs, while Moolman et al. have elaborated on the contributions of adenosine, cAMP/PKA system as well as p 38mapk in eliciting a cardioprotective response during early preconditioning. This section also has two elegant articles on the role of angiotensin II in cardiovascular pathophysiology: Engberding and Grindling and Schaffer and Mozaffari have provided indepth accounts of various signaling pathways induced by angiotensin II and how the dysregulation of this pathway contributes to heightened growth, proliferation, hypertrophy, and cell survival death responses associated with various cardiovascular abnormalities. v vi PrefaceThe second section foc...

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Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice

Cited by 46 publications

References 30 publications

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

H₂S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure

Signal Transduction in the Cardiovascular System in Health and Disease

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