Increased Cardiac Expression of Tissue Inhibitor of Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinase-2 Is Related to Cardiac Fibrosis and Dysfunction in the Chronic Pressure-Overloaded Human Heart

Heymans, Stéphane; Schroen, Blanche; Vermeersch, Pieter; Milting, Hendrik; Gao, Fangye; Kassner, Astrid; Gillijns, Hilde; Herijgers, Paul; Flameng, Willem; Carmeliet, Peter; Werf, Frans Van de; Pinto, Yigal M.; Janssens, Stefan

doi:10.1161/circulationaha.104.516963

Cited by 278 publications

(210 citation statements)

References 31 publications

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“…Biopsies of patients with pressure-overload and left ventricular (LV) hypertrophy due to severe aortic stenosis (n ϭ 8) and control CABG patients (n ϭ 6) without LV hypertrophy were collected and characterized as described (32). A primary antibody against KLF15 (generated by Zymed) was used for immunostaining.…”

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confidence: 99%

“…A primary antibody against KLF15 (generated by Zymed) was used for immunostaining. Myocyte cross-sectional area was determined, and the relative surface area of KLF15-immunoreactivity was expressed as percentage immunoreactive area over total area, using a Zeiss Axioplan2 microscope, a 3CCD video camera (DXC-93OP, Sony), and KS300 software as described (32). Immunocytochemistry and FACS Analysis.…”

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confidence: 99%

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Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

Fisch

Gray

Heymans

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.

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confidence: 99%

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

Fisch

Gray

Heymans

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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191

230

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“…Among the four TIMPs identified to date, TIMP-2 is unique in that it activates pro-MMP-2 to active MMP-2 and also inhibits the active MMP-2. 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).…”

Section: Discussionmentioning

confidence: 99%

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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“…Rats were followed by serial echocardiography at 10, 12, 15, 16, 18, 19, and 21 wk of age and killed at 15-18 wk upon clinical signs of HF (HF-prone/ HF-prone rats) or at 21 wk when clinical signs of failure had not appeared (compensated/compensated rats). Total RNA was isolated from LV biopsies and amplifi ed as described previously (10,25), hybridized to Aff ymetrix rat RAE230 2.0 GeneChips, and analyzed with Microarray Analysis Suite software (version 5.0). 50 μg of LV protein extracts were immunoblotted with polyclonal rabbit anti-LIMP-2 (1:500; Novus Biologicals) and polyclonal rabbit anti-GAPDH (1:10,000; Abcam).…”

Section: Methodsmentioning

confidence: 99%

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Schroen¹,

Leenders²,

Erk³

et al. 2007

J Cell Biol

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Chronic cardiac loading as occurs during longstanding hypertension induces cardiac hypertrophy, which often progresses to left ventricle (LV) dysfunction and overt heart failure (HF). The molecular changes that precede and herald this transition from hypertrophy toward HF are incompletely understood (1).The intercalated disc (ID) of cardiac myocytes has emerged as a crucial structure in the heart. The cardiac ID consists of three major structures: gap junctions, adherens junctions, and desmosomes. In dilated cardiomyopathy, the number of gap junctions is decreased while the adherens junctions increase, leading to reduced cardiac communication and increased stiff ness (2). An important role for ID structure is further demonstrated by the fact that complete loss of ID proteins like N-cadherin, plakoglobin, and β-catenin (3-6) is lethal. Moreover, mutations in ID proteins like desmoplakin, desmoglobin, plakoglobin, and plakophilin-2 (7-9) cause human cardiomyopathies. However, factors that more subtly modulate the ID have not yet been described.We have previously reported on the unique propensity of the homozygous hypertensive transgenic rat TGR(mRen-2) 27 (Ren-2). A proportion of these rats rapidly progresses toward HF, The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also fi nd LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated -catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect.Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.Abbreviations used: ANF, atrial natriuretic factor; Ang, angiotensin; aska, α-skeletal actin; BNP, brain natriuretic peptide; HF, heart failure; ID, intercalated disc; IP, immunoprecipitation; LIMP-2, lysosomal integral membrane protein 2; LV, left ventricle; RCM, rat ventricular cardiac myocyte; shLIMP-2, short-hairpin RNA against LIMP-2; shRNA, short-hairpin RNA; TSP, thrombospondin.The online version of this article contains supplemental material.

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Increased Cardiac Expression of Tissue Inhibitor of Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinase-2 Is Related to Cardiac Fibrosis and Dysfunction in the Chronic Pressure-Overloaded Human Heart

Cited by 278 publications

References 31 publications

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

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

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

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