Overexpression of elastin fragments in infarcted myocardium attenuates scar expansion and heart dysfunction

Mizuno, Tomohiro; Mickle, Donald A.G.; Kiani, Chris; Li, Ren‐Ke

doi:10.1152/ajpheart.00862.2004

Cited by 45 publications

(43 citation statements)

References 20 publications

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“…However, the soluble elastin that we investigated in the present study of aortic specimens showed a decreasing pattern, which is different from the other elastin-associated proteins previously described. 14,[24][25][26][27][28] In the present study, we found that in the non-atherosclerotic aorta soluble elastin was (1) distributed both within the intima and around the mature elastin within the media, (2) different from mature elastic fiber (Figure 1), (3) had the lowest mRNA expression among the 4 histological groups (Figure 3d), (4) present in a low ratio to tropoelastin, which is conjectured to be a marker of elastin synthesis, compared with ruptured plaque (Figure 5), and (5) associated with the activity of MMP-9 among the 4 groups (Figure 3b). These results indicate that in the non-atherosclerotic aorta from subjects approximately 53-84 years of age, soluble elastin is densely distributed and neither endogenous elastogenesis or elastolysis is activated excessively, so soluble elastin may be deposited gradually and preserved within the intima and around the mature elastic fibers within the media over a number of years because the intima is not diseased.…”

Section: Discussionmentioning

confidence: 99%

Soluble Elastin Decreases in the Progress of Atheroma Formation in Human Aorta

Ashihara

Nakanishi

Suzuki³

et al. 2009

Circ J

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Section: Discussionmentioning

confidence: 99%

Soluble Elastin Decreases in the Progress of Atheroma Formation in Human Aorta

Ashihara

Nakanishi

Suzuki³

et al. 2009

Circ J

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“…16,17 Recently it has been shown that transplanting cells that are overexpressing elastin gene fragments into a myocardial scar modifies the scar content, increases cardiac elasticity, and facilitates ventricular function. 18,19 Increasing elastogenesis in a postinfarct heart thus introduces a novel therapeutic concept, but it needs further mechanistic evaluation.…”

mentioning

confidence: 99%

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Bunda

Liu

Wang

et al. 2007

The American Journal of Pathology

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Aldosterone is known to regulate electrolyte homeostasis, but it may also contribute to other processes, including the maladaptive remodeling of postinfarct hearts. Because aldosterone has been implicated in the stimulation of collagen production in the heart, we investigated whether it would also affect elastin deposition in cultures of human cardiac fibroblasts. We first demonstrated that treatment with 1 to 50 nmol/L aldosterone leads to a significant increase in collagen type I mRNA levels and in subsequent collagen fiber deposition. Pretreatment of cells with the mineralocorticoid receptor antagonist spironolactone, but not with the glucocorticoid receptor antagonist RU 486, inhibited collagen synthesis in aldosterone-treated cultures. Most importantly, we demonstrated that aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition in a dose-dependent manner. Strikingly, neither spironolactone nor RU 486 eliminated aldosterone-induced increases in elastin production. We further discovered that the proelastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor and that the insulin-like growth factor-I receptor kinase inhibitor AG1024 or an anti-insulin-like growth factor-I receptor-neutralizing antibody inhibits both insulin-like growth factor-I and aldosterone-induced elastogenesis. Thus, we have demonstrated for the first time that aldosterone, which stimulates collagen production through the mineralocorticoid receptor-dependent pathway, also increases elastogenesis via a parallel mineralocorticoid receptor-independent pathway involving I insulin-like growth factor-I receptor signaling.

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“…As it had been shown very recently that Neu-1 was the isoform found in the elastin complex receptor (30,50), we evaluated its involvement in elastin signaling by generating an enzymatic inactive form of Neu-1, Neu-1-G68V, which exhibits no sialidase activity (42). Due to the difficulty in achieving a convenient transfection rate using primary human dermal fibroblasts, we used COS-7 cells, a model previously used in elastinand Neu-1-related experiments (42,45).…”

Section: Discussionmentioning

confidence: 99%

“…Because of the difficulty in achieving an efficient co-transfection of plasmids expressing Neu-1-G68V and construct encoding luciferase under the control of MMP-1 promoter in human skin fibroblasts, we used COS-7 cells, a model, which was successfully used in previous Neu-1 and elastin-related experiments (42,45).…”

Section: Effects Of Catalytically Inactive Neu-1 and Neu-1 Sirna Silementioning

confidence: 99%

The Elastin Receptor Complex Transduces Signals through the Catalytic Activity of Its Neu-1 Subunit

Duca

Blanchevoye

Cantarelli

et al. 2007

Journal of Biological Chemistry

110

117

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The binding of elastin peptides on the elastin receptor complex leads to the formation of intracellular signals but how this is achieved remains totally unknown. Using pharmacological inhibitors of the enzymatic activities of its subunits, we show here that the elastin peptide-driven ERK1/2 activation and subsequent pro-MMP-1 production, observed in skin fibroblasts when they are cultured in the presence of these peptides, rely on a membrane-bound sialidase activity. As lactose blocked this effect, the elastin receptor sialidase subunit, Neu-1, seemed to be involved. The use of a catalytically inactive form of Neu-1 and the small interfering RNA-mediated decrease of Neu-1 expression strongly support this view. Finally, we report that N-acetyl neuraminic acid can reproduce the effects of elastin peptides on both ERK1/2 activation and pro-MMP-1 production. Altogether, our results indicate that the enzymatic activity of the Neu-1 subunit of the elastin receptor complex is responsible for its signal transduction, presumably through sialic acid generation from undetermined substrates.Elastin is the extracellular matrix protein responsible for the elasticity of tissues. It is more abundant in tissues where resilience is required, such as skin, lung, ligaments, or large arteries (1). Elastin is constituted of tropoelastin molecules covalently bound to each other by covalent cross-links (2) and its hydrophobic and highly cross-linked nature make of it a very durable polymer experiencing essentially no turnover in healthy tissues (3).The biological role of elastin was originally thought to be restricted to this mechanical function. However, when Senior et al. (4) demonstrated that elastin digestion products were chemotactic for neutrophils and macrophages, it became suddenly apparent that peptides derived from amorphous elastin could modulate cell physiology. In fact, it has been shown because that fibroblasts (5-12), smooth muscle cells (7, 13-15), endothelial cells (16 -19), leukocytes (20, 21), and lymphocytes (22) were sensitive to the presence of these peptides yielding a broad range of biological activities (see Ref. 23 for a review). A corollary of these observations was that those cells do express a receptor for elastin peptides.The elastin receptor complex is constituted of three subunits, one peripheral 67-kDa subunit, which actually binds elastin, and two membrane-associated proteins of 61 and 55 kDa, respectively (10). The 67-kDa elastin-binding protein (EBP) 2 binds the VGVAPG elastin sequence with high affinity. Additionally, EBP can be eluted from elastin affinity column by galactosugars suggesting that the elastin-EBP interaction could be regulated by galactosugars bound on a lectin site on EBP (10, 24). Consequently, galactosugars such as lactose are commonly used antagonists of EBP.Later, the nature of this subunit was revealed by the work of Privitera et al. (25) who have shown that EBP is an enzymatically spliced variant of lysosomal ␤-galactosidase (␤-Gal, EC 3.2.1.23). Consequently, it was hypot...

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Overexpression of elastin fragments in infarcted myocardium attenuates scar expansion and heart dysfunction

Cited by 45 publications

References 20 publications

Soluble Elastin Decreases in the Progress of Atheroma Formation in Human Aorta

Soluble Elastin Decreases in the Progress of Atheroma Formation in Human Aorta

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

The Elastin Receptor Complex Transduces Signals through the Catalytic Activity of Its Neu-1 Subunit

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