Myocardial Osteopontin Expression Is Associated With Left Ventricular Hypertrophy

Graf, Kristof; Yung, Susan; Ashizawa, Naoto; Meehan, Woerner P.; Giachelli, Cecilia M.; Marboe, Charles C.; Fleck, Eckart; Hsueh, Willa A.

doi:10.1161/01.cir.96.9.3063

Cited by 136 publications

(147 citation statements)

References 26 publications

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“…Cardiac OPN expression is increased by activation of both cardiac AngII type 1 receptors and mineralocorticoid receptors (37). We previously reported that cardiac OPN expression is elevated in rodent models of cardiac hypertrophy and in ventricles of explanted hearts from humans receiving cardiac transplants (13). OPN promotes cardiac fibroblast attachment to the extracellular matrix (ECM), and cardiac fibroblast growth and ECM production (12,43), whereas OPNdeficient mice have attenuated cardiac fibrosis, suggesting that OPN is a key profibrotic factor in the heart (11,44,45).…”

Section: Discussionmentioning

confidence: 99%

“…However, little is known about the cellular mechanism of these effects, and the prevalence of and mortality from heart failure continues to increase and is particularly common in subjects with diabetes (10). We have shown that osteopontin (OPN), a secreted inflammatory glycophosphoprotein, plays a pivotal role in cardiac fibrosis (11) and is often increased in the tissues of diabetic mouse models (11)(12)(13). Ventricular OPN expression is increased during heart failure, paralleling the increase in atrial natriuretic peptide (ANP) expression, and AngII prominently upregulates OPN in cardiac cells (12,13).…”

mentioning

confidence: 99%

“…We have shown that osteopontin (OPN), a secreted inflammatory glycophosphoprotein, plays a pivotal role in cardiac fibrosis (11) and is often increased in the tissues of diabetic mouse models (11)(12)(13). Ventricular OPN expression is increased during heart failure, paralleling the increase in atrial natriuretic peptide (ANP) expression, and AngII prominently upregulates OPN in cardiac cells (12,13). Moreover, OPN knockout (KO) mice develop less cardiac fibrosis than control mice (11) and are partially protected against streptozotocin-induced diabetic cardiomyopathy (14).…”

mentioning

confidence: 99%

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Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

et al. 2008

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OBJECTIVE— Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis. RESEARCH DESIGN AND METHODS— Wild-type cardiomyocyte- and macrophage-specific PPARγ −/− mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARγ ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARγ in cardiac fibrosis. RESULTS— Cardiomyocyte-specific PPARγ −/− mice (cPPARγ −/− ) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARγ −/− mice but induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARγ–independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARγ −/− mice. CONCLUSIONS— We arrived at the following conclusions: 1 ) both cardiomyocyte-specific PPARγ deficiency and activation promote cardiac hypertrophy, 2 ) both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration, 3 ) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4 ) macrophage PPARγ activation prevents myocardial macrophage accumulation, and 5 ) PPARγ ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

et al. 2008

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“…3 In vivo OP expression is observed predominantly in cardiomyocytes in experimental models of Ang IIdependent myocardial hypertrophy. 4 Increased cardiac OP expression, either in fibroblasts and/or cardiomyocytes, has been reported with the onset of heart failure, 7 after myocardial infarction, 8 and in patients with progressive heart failure. 9 This suggests that OP is involved in mechanisms regulating the cardiac response to pressure or volume load or myocardial injury.…”

Section: Op and The Heartmentioning

confidence: 99%

Osteopontin: A Protective Mediator of Cardiac Fibrosis?

Graf

Stawowy

2004

Hypertension

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O steopontin (OP) is a multifunctional cytokine and adhesion protein that contains an RGD (argininglycin-aspartate) binding sequence that enables it to interact with several integrins, CD44 variants, and other adhesion receptors. OP receptor binding then directly or indirectly activates intracellular signaling pathways, mediating its effects on cell-matrix and cell-cell interactions. OP is increased in response to pro-inflammatory cytokines and mechanical strain in various cell types, 1 and the function of its secreted protein can be altered by proteases, including thrombin. 2 Thus, OP can exists as an immobilized matrix molecule (eg, in bone, atherosclerotic plaques, or calcified heart valves) or as soluble cytokine.Cell signaling by OP is predominantly mediated through integrin engagement. Cleavage of OP by thrombin exposes integrin binding sites 2 (eg, for ␣ 9 ␤ 1 ), which are important for OP-mediated adhesion/migration. OP is chemotactic for various cell types, most notably monocytes/macrophages, which are attracted to sites of injury and inflammation. The bestcharacterized OP-induced signal pathway is the integrinstimulated FAK-Src-Rho pathway in osteoclasts. 1 However, identification and dissection of signal transduction pathways are complicated by the fact that OP potentially binds to several cell surface receptors.

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“…Necrotic and noninjured specimens were analyzed separately to exclude a significant contribution of Opn transcripts from myocardial remodeling in response to injury. 33 Examination of necrotic tissue revealed comparable induction of Opn (ϳ12-fold) in both C57BL/6 and C3H/He 1 day after injury (Figure 2A). Coincident with increasing calcification of necrosis, up-regulation of Opn began at day 2 and peaked at day 3 in the C3H/He strain: compared to baseline, up-regulation reached ϳ1300-fold, 20-times more than observed in C57BL/6 mice showing a maximal 65-fold increase relative to baseline.…”

Section: Dramatic Transcriptional Induction Of Opn In C3h/hementioning

confidence: 82%

A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice

Aherrahrou

Axtner

Kaczmarek

et al. 2004

The American Journal of Pathology

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Calcification of necrotic tissue is frequently observed in chronic inflammation and atherosclerosis. A similar response of myocardium to injury, referred to as dystrophic cardiac calcinosis (DCC), occurs in certain inbred strains of mice. We now examined a putative inhibitor of calcification, osteopontin, in DCC after transdiaphragmal myocardial freeze-thaw injury. Strong osteopontin expression was found co-localizing with calcification in DCC-susceptible strain C3H/ HeNCrlBr, which exhibited low osteopontin plasma concentrations otherwise. Osteopontin mRNA induction was 20-fold higher than in resistant strain C57BL/ 6NCrlBr, which exhibited fibrous lesions without calcification and little osteopontin expression. Sequence analysis identified several polymorphisms in calcium-binding and phosphorylation sites in osteopontin cDNA. Their potential relevance for DCC was tested in congenic mice, which shared the osteopontin locus with C57BL/6NCrlBr, but retained a chromosomal segment from C3H/HeNCrlBr on proximal chromosome 7. These mice exhibited strong osteopontin expression and DCC comparable to C3H/HeNCrlBr suggesting that a trans-activator of osteopontin transcription residing on chromosome 7 and not the osteopontin gene on chromosome 5 was responsible for the genetic differences in osteopontin expression. A known osteopontin activator encoded by a gene on chromosome 7 is the transforming growth factor-␤1, which was more induced (3.5؋) in C3H/HeNCrlBr than in C57BL/6NCrlBr mice.

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Myocardial Osteopontin Expression Is Associated With Left Ventricular Hypertrophy

Abstract: The present study provides the first evidence that cardiomyocytes are a prominent source of OP in vivo and suggests that induction of OP expression is strongly associated with ventricular hypertrophy.

Cited by 136 publications

References 26 publications

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

Osteopontin: A Protective Mediator of Cardiac Fibrosis?

A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice

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