Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure

Barton, Paul J.R.; Birks, Emma J.; Felkin, Leanne E.; Cullen, Martin E.; Koban, Michael; Yacoub, Magdi H.

doi:10.1016/s1053-2498(02)00557-0

Cited by 63 publications

(39 citation statements)

References 24 publications

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“…nificantly increased in DCM (406). These studies and others (15,158,206,230,285,406,444,456) suggest that selective changes in myocardial MMP profiles occur that are likely due to transcriptional regulation. Moreover, there is an emergence of MMPs such as MMP-13 and MT1-MMP with DCM which contain a diverse portfolio of proteolytic substrates and therefore may significantly contribute to adverse LV remodeling.…”

Section: Human-based Studiessupporting

confidence: 56%

“…With the use of a gelatin-impregnated electrophoretic platform, these initial studies as well as those that quickly followed (15,229,370,444) demonstrated the presence of the gelatinases MMP-2 and MMP-9 within normal human myocardial specimens. With the use of immunochemical and gene expression approaches, the presence of MMPs within the normal adult human myocardium were identified that spanned all of the general classes of MMPs, and these studies formed the basis for presenting these specific MMP types in Table 1 (15,158,206,229,230,370,406,444). For example, these studies demonstrated the presence of the interstitial collagenases MMP-1, -13, and -8.…”

Section: A Mmp Expression In Normal Adult Myocardiummentioning

confidence: 95%

“…While it remains to be established, it is likely that these differences in chamber specific MMP profiles are due to a combination of factors that include inherent differences in loading conditions, embryological origin, and cellular response to biological stimuli. With respect to TIMPs, all four TIMPs have been identified within the normal human myocardium (15,158,206,230,285,406,444). A robust signal for the cardiovascular-specific TIMP, TIMP-4, has been demonstrated in all four chambers of the human heart (229,285,444).…”

Section: A Mmp Expression In Normal Adult Myocardiummentioning

confidence: 97%

“…Since DCM is a progressive myocardial disease process that culminates in severe heart failure and hemodynamic collapse, then mechanical assist devices and/or heart transplantation are often required. As such, access to myocardial samples from DCM patients is possible and has allowed for an extensive survey of the MMP/TIMP system (15,146,158,206,229,230,285,370,406,444,456). In addition, several large-animal models have been utilized to examine changes in myocardial MMP/TIMPs during the progression of DCM.…”

Section: Mmps In Cardiomyopathymentioning

confidence: 99%

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Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Spinale¹

2007

Physiological Reviews

998

1,023

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It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic myocardial disease such as cardiomyopathy. Furthermore, a family of matrix proteases, the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs), has been recognized to play an important role in matrix remodeling in these cardiac disease states. The purpose of this review is fivefold: 1) to examine and redefine the myocardial matrix as a critical and dynamic entity with respect to the remodeling process encountered with MI, hypertension, or cardiomyopathic disease; 2) present the remarkable progress that has been made with respect to MMP/TIMP biology and how it relates to myocardial matrix remodeling; 3) to evaluate critical translational/clinical studies that have provided a cause-effect relationship between alterations in MMP/TIMP regulation and myocardial matrix remodeling; 4) to provide a critical review and analysis of current diagnostic, prognostic, and pharmacological approaches that utilized our basic understanding of MMP/TIMPs in the context of cardiac disease; and 5) most importantly, to dispel the historical belief that the myocardial matrix is a passive structure and supplant this belief that the regulation of matrix protease pathways such as the MMPs and TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.

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Section: Human-based Studiessupporting

confidence: 56%

Section: A Mmp Expression In Normal Adult Myocardiummentioning

confidence: 95%

Section: A Mmp Expression In Normal Adult Myocardiummentioning

confidence: 97%

Section: Mmps In Cardiomyopathymentioning

confidence: 99%

See 2 more Smart Citations

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Spinale¹

2007

Physiological Reviews

998

1,023

View full text Add to dashboard Cite

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“…Increased MMP-9 and reduced TIMP expression (TIMP-1, TIMP-3, and TIMP-4) have been shown in HF. 50 We have previously reported high myocardial MMP-1 and MMP-8 expression in patients with deteriorating conditions requiring LVAD support 51,52 along with increased TIMP-4 expression. Others have reported that after LVAD support, MMP-1 and MMP-9 tended to decrease with a normalization of the MMP-1:TIMP-1 ratio 48 and an increase in TIMP expression (TIMP-1 and TIMP-3).…”

Section: Circulation Research August 30 2013mentioning

confidence: 97%

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

102

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Abstract-Heart failure is associated with remodeling that consists of adverse cellular, structural, and functional changes in the myocardium. Until recently, this was thought to be unidirectional, progressive, and irreversible. However, irreversibility has been shown to be incorrect because complete or partial reversal can occur that can be marked after myocardial unloading with a left ventricular assist device (LVAD). Patients with chronic advanced heart failure can show near-normalization of nearly all structural abnormalities of the myocardium or reverse remodeling after LVAD support. However, reverse remodeling does not always equate with clinical recovery. The molecular changes occurring after LVAD support are reviewed, both those demonstrated with LVAD unloading alone in patients bridged to transplantation and those occurring in the myocardium of patients who have recovered enough myocardial function to have the device removed. Reverse remodeling may be attributable to a reversal of the pathological mechanisms that occur in remodeling or the generation of new pathways. A reduction in cell size occurs after LVAD unloading, which does not necessarily correlate with improved cardiac function. However, some of the changes in both the cardiac myocyte and the matrix after LVAD support are specific to myocardial recovery. In the myocyte, increases in the cytoskeletal proteins and improvements in the Ca 2+ handling pathway seem to be specifically associated with myocardial recovery. Changes in the matrix are complex, but excessive scarring appears to limit the ability for recovery, and the degree of fibrosis in the myocardium at the time of implantation may predict the ability to recover. (Circ Res. 2013;113:777-791.)

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Genomic biomarkers for cardiotoxicity in rats as a sensitive tool in preclinical studies

Nishimura

Morikawa

Kondo

et al. 2013

J of Applied Toxicology

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The development of safer drugs is a high priority for pharmaceutical companies. Among the various toxicities caused by drugs, cardiotoxicity is an important issue because of its lethality. In addition, cardiovascular toxicity leads to the attrition of many drug candidates in both preclinical and clinical phases. Although histopathological and blood chemistry examinations are the current gold standards for detecting cardiotoxicity in preclinical studies, the large number of withdrawals from clinical studies owing to safety problems indicate that a more sensitive tool is required. We recently identified 32 genes that were candidate genomic biomarkers for cardiotoxicity in rats. Based on their functions, the present study focused on 8 of these 32 genes (Spp1, Fhl1, Timp1, Serpine1, Bcat1, Lmcd1, Rnd1 and Tgfb2). Diagnostic accuracy for the genes was determined by a receiver-operating characteristic (ROC) analysis using more cardiotoxic and non-cardiotoxic compounds. In addition, an optimized support vector machine (SVM) model that was composed of Spp1 and Timp1 was newly constructed. This new multi-gene model exhibited a much higher diagnostic accuracy than that observed for plasma cardiac troponin I (cTnI), which is one of the most useful plasma biomarkers for cardiotoxicity detection. Furthermore, we determined that this multi-gene model could predict potential cardiotoxicity in rats in the absence of any cardiac histopathological lesions or elevations of plasma cTnI. Overall, this multi-gene model exhibited advantages over classic tools commonly used for cardiotoxicity evaluations in rats. Our current results suggest that application of the model could potentially lead to the production of safer drugs.

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Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure

Cited by 63 publications

References 24 publications

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Genomic biomarkers for cardiotoxicity in rats as a sensitive tool in preclinical studies

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