Role of Myocytes in Myocardial Collagen Production

Pathak, Manoj Kumar; Sarkar, Sagartirtha; Vellaichamy, Elangovan; Sen, Subha

doi:10.1161/01.hyp.37.3.833

Cited by 63 publications

(50 citation statements)

References 28 publications

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“…AngII, known to induce cardiac hypertrophy involving renin-angiotensin system, was shown to induce IL-6 production both in cultured cardiac fibroblasts and during maladaptive pressure overload hypertrophy via activation of gp130 (9, 10, 13). IL-6 has been shown to increase collagen synthesis both in in vitro cultured fibroblasts and in in vivo rat hearts (8,9,11). Consistent with these previous studies, we also observed increased levels of IL-6 after AngII treatment of cardiac fibroblasts (data not shown) as well as up-regulation of collagen expression by IL-6 (Figs.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, lysyl oxidase (LOX) is also instrumental during collagen biogenesis that catalyzes lysine-derived cross-bridges between two or more lysine residues of nascent procollagen peptides during their maturation into collagen molecules (5, 7). Altered and deregulated expression of these factors has been demonstrated in failing myocardium (5).Involvement of various neurohumoral and growth factors has also been illustrated in the development of cardiac fibrosis both in vitro and in vivo (3,8). Cellular cross-talk between AngII-treated cardiomyocytes and fibroblasts has been shown to play an important role during collagen up-regulation with involvement of IL-6 during fibrosis (8 -10).…”

mentioning

confidence: 99%

“…Involvement of various neurohumoral and growth factors has also been illustrated in the development of cardiac fibrosis both in vitro and in vivo (3,8). Cellular cross-talk between AngII-treated cardiomyocytes and fibroblasts has been shown to play an important role during collagen up-regulation with involvement of IL-6 during fibrosis (8 -10).…”

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confidence: 99%

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Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Mir

Chatterjee

Mitra

et al. 2012

Journal of Biological Chemistry

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120

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IL-6 has been shown to play a major role in collagen up-regulation process during cardiac hypertrophy, although the precise mechanism is still not known. In this study we have analyzed the mechanism by which IL-6 modulates cardiac hypertrophy. For the in vitro model, IL-6-treated cultured cardiac fibroblasts were used, whereas the in vivo cardiac hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). During induction of hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK, and ERK proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (fludarabine, 50 M), STAT3 (S31-201, 10 M), p38 MAPK (SB203580, 10 M), and ERK1/2 (U0126, 10 M) resulted in down-regulation of IL-6-induced phosphorylation of specific proteins; however, only S31-201 and SB203580 inhibited collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in collagen synthesis and hypertrophy markers such as atrial natriuretic factor and ␤-myosin heavy chain. In addition, decreased heart weight to body weight ratio and improved cardiac function as measured by echocardiography was evident in animals treated with STAT3 inhibitor or siRNA. Compared with IL-6 neutralization, more pronounced down-regulation of collagen synthesis and regression of hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for cardiac hypertrophy.Cardiac fibrosis is considered to be a major player during hypertrophy, where excess synthesis and a disproportionate accumulation of extracellular matrix proteins in the myocardium leads to its stiffness and diastolic dysfunction, leading to heart failure (1-3). Fibrillar collagen 1 and collagen 3 are the most abundant extracellular matrix proteins in the myocardium that maintain myocardial structural integrity (4). Collagen biosynthesis process is mainly compartmentalized in cardiac fibroblasts with a continuous turnover of newly synthesized collagen and degradation of old existing collagen, which involves post-transcriptional as well as post translational events. A physiological balance exists between collagen synthesis and degradation that is necessary to maintain tissue integrity of the myocardium. Extracellular catalytic cleavage of collagen is mediated by matrix metalloproteinases (MMPs) 2 that are eventually regulated by their naturally occurring endogenous inhibitors, i.e. tissue inhibitors of metalloproteinases (TIMPs) (1, 5).The fine balance between MMPs and TIMPs plays a crucial role in regulation of cardiac collagen turnover (5, 6). Furthermore, lysyl oxidase (LOX) is also instrumental during collagen biogenesis that catalyzes lysine-derived cross-bridges between two or more lysine residues of nascent procollagen peptides during their maturation into collagen molecules (5, 7). Altered and deregulated expression of these factors has been demonstrated in failing myocardium (5).Involvem...

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

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Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Mir

Chatterjee

Mitra

et al. 2012

Journal of Biological Chemistry

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120

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“…For coculture experiments, culture supernatants from different experimental groups of myocytes were transferred to fibroblast plates and were conditioned for 24 h (myocyte-conditioned medium [MCM]-treated fibroblasts). Also, fibroblasts were cocultured with myocytes on coverslips and inserts (7). For time point analysis, fibroblasts were incubated with MCM for 3 h to 12 h.…”

Section: Methodsmentioning

confidence: 99%

“…A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5,6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.…”

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confidence: 99%

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Datta

Bansal

Rana

et al. 2017

Molecular and Cellular Biology

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Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.KEYWORDS cardiac hypertrophy, collagen, Hsp90, myocyte-fibroblast cross talk, STAT-3 M yocardial fibrosis is a hallmark of cardiac hypertrophy and a proposed substrate for heart failure (1, 2). The extracellular space is frequently the site for such abnormal accumulation of fibrillar collagen, accounting for myocardial stiffness and ventricular dysfunction during cardiac hypertrophy (3). The cardiac fibroblast is the principal cell type in the myocardium and synthesizes and secretes collagen in response to pressure-overload hypertrophy (4). A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5, 6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.In an earlier report, we described the mechanism of interleukin-6 (IL-6)-mediated activation of the signal transducer and activator of transcription 3 (STAT-3) and consequent collagen synthesis in the hypertrophied rat heart (9). STAT-3 activation has also

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Acidic and basic hydrolysis of poly(N‐vinylformamide)

Zhu

Hrymak

2002

J of Applied Polymer Sci

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Poly(N-vinylformamide) (PNVF) was synthesized and hydrolyzed to poly(vinylamine) (PVAm) in both HCl and NaOH solutions. The hydrolysis kinetics and the equilibrium hydrolysis were examined experimentally at different temperatures, polymer concentrations, and acid-or base-to-amide molar ratios. The hydrolysis kinetics strongly depended on temperature, polymer, and HCl or NaOH concentrations, but showed little dependence on PNVF molecular weight. The acid hydrolysis of PNVF exhibited limited conversions because of the electrostatic repulsion among the cationic amine groups generated during hydrolysis and proton hydrates. In the basic hydrolysis, complete amide conversions were observed when the NaOH/amide molar ratios were greater than unity. The effects of temperature and PNVF concentration on the equilibrium amide conversion appeared to be negligible in both acidic and basic hydrolysis. The equilibrium conversions of base hydrolysis were higher than those of acidic hydrolysis under the same reaction conditions. At NaOH/amide ratios of less than unity, the equilibrium hydrolysis experiments revealed that one base molecule could induce the hydrolysis of more than one amide group.

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Role of Myocytes in Myocardial Collagen Production

Cited by 63 publications

References 28 publications

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Acidic and basic hydrolysis of poly(N‐vinylformamide)

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