Hsp90/Cdc37 assembly modulates TGFβ receptor-II to act as a profibrotic regulator of TGFβ signaling during cardiac hypertrophy

Bansal

Molecular and Cellular Biology

et al. 2017

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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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Section: Fig 13mentioning

confidence: 99%

“…Fibroblasts were confirmed by staining with antivimentin antibody. The treatment of fibroblasts with AngII, 17-AAG, and Hsp90 siRNA was done as previously described (26).…”

Section: Fig 13mentioning

confidence: 99%

“…for 3 consecutive days at a dose of 0.2 mg/kg/day before renal artery ligation. Control and ligated rats were treated with equivalent amounts of DMSO (26).…”

Section: Fig 13mentioning

confidence: 99%

Section: Fig 13mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Bansal

Molecular and Cellular Biology

et al. 2017

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Modulation of NFKB1/p50 by ROS leads to impaired ATP production during MI compared to cardiac hypertrophy

Mitra

J of Cellular Biochemistry

et al. 2017

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Pathological hypertrophy and myocardial infarction (MI) are two etiologically different cardiac disorders having differential molecular mechanisms of disease manifestation. However, no study has been conducted so far to analyze and compare the differential status of energy metabolism in these two disease forms. It was shown recently by our group that production of ATP is significantly impaired during MI along with inhibition of pyruvate dehydrogenase E1-β (PDHE1 B) by pyruvate dehydrogenase kinase 4 (PDK4). However, the ATP levels showed no significant change during pathological hypertrophy compared to control group. To seek a plausible explanation of this phenomenon, the peroxisome proliferator-activated receptor alpha (PPAR) pathway was studied in all the experimental groups which revealed that PGC1α- ERRα axis remains active in MI while the same remained inactive during pathological hypertrophy possibly by NF-κB that plays a significant role in deactivating this pathway during hypertrophy. At the same time, it was observed that reactive oxygen species (ROS) negatively regulates NF-κB activity during MI by oxidation of cysteine residues of p50- the DNA binding subunit of NF-κB. Thus, this study reports for the first time, a possible mechanism for the differential status of energy metabolism during two etiologically different cardiac pathophysiological conditions involving PGC1α-ERRα axis along with p50 subunit of NF-κB.

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Key Cellular Effectors in ROS-Mediated Cardiac Diseases

Chaudhuri

Modulation of Oxidative Stress in Heart Disease

et al. 2019