Leptin and endothelin‐1 mediated increased extracellular matrix protein production and cardiomyocyte hypertrophy in diabetic heart disease

Majumdar, Pijush; Chen, Shali; George, Biju; Sen, Sabyasachi; Karmazyn, Morris; Chakrabarti, Subrata

doi:10.1002/dmrr.964

Cited by 40 publications

(36 citation statements)

References 43 publications

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“…The bladder weight and the thickness of the bladder wall were immediately increased at 2 h post-CYP injection and continued increasing until 48 h as examined. There are several possible mechanisms and pathways involved in visceral organ hypertrophy, including increases in the production of extracellular matrix (13,39,40) and increases in muscular growth (13,41). In the current study, we examined the expression level of type I collagen, the main constituent of the extracellular matrix, in the inflamed bladder and found that the mRNA level of type I collagen was significantly increased at 2 and 8 h post-CYP injection and was back to normal level at 48 h post-CYP injection.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Nerve Growth Factor Regulates Collagen Expression and Bladder Hypertrophy through Akt and MAPK Pathways during Cystitis

Chung

Zhang

Qiao

2010

Journal of Biological Chemistry

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Type I collagen forms the main constituent of the extracellular matrix in visceral organs. We reported here that cyclophosphamide (CYP)-induced cystitis significantly increased the production of type I collagen in the inflamed bladder leading to increases in the bladder weight and the thickness of the bladder wall. The endogenous nerve growth factor (NGF) in the urinary bladder regulated type I collagen expression because the neutralizing NGF antibody attenuated cystitisinduced type I collagen up-regulation in the inflamed bladder. Neutralizing NGF antibody also subsequently reversed cystitis-induced increases in bladder weight. Further studies on the intermediate signaling pathways mediating NGF-induced type I collagen expression in the inflamed bladder during cystitis revealed that Akt, JNK, and ERK1/2 activities were increased in the inflamed bladder, whereas p38 MAPK remained unchanged. Suppression of endogenous NGF level with neutralizing NGF antibody significantly blocked the increased activity of Akt, JNK, and ERK1/2 in the inflamed bladder during cystitis. These results indicate that endogenous NGF plays an important role in the activation of Akt and MAPK in the urinary bladder and in bladder hypertrophy during cystitis.

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Section: Discussionmentioning

confidence: 99%

Endogenous Nerve Growth Factor Regulates Collagen Expression and Bladder Hypertrophy through Akt and MAPK Pathways during Cystitis

Chung

Zhang

Qiao

2010

Journal of Biological Chemistry

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“…Numerous studies suggest that leptin is an important mediator of pathological cardiac remodeling [13,14,17,19,[21][22][23][24], which is characterized by cardiomyocyte hypertrophy and a disruption of the ECM resulting in increased collagen deposition [1,3]. Here we investigated the effect of leptin on regulation of myocardial matrix components, specifically MMP-2 activity, TIMP-1 expression and collagen-I/-III expression, in HL-1 cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes

Schram

Girolamo

Madani

et al. 2010

Cellular and Molecular Biology Letters

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Abbreviations used: AP-1 -activator protein-1; ATF-2 -activating transcription factor-2; ECM -extracellular matrix; HF-heart failure; LV -left ventricular; MAPK -mitogen activated protein kinase; MMP -matrix metalloproteinase; mRNA-messenger ribonucleic acid; PBS -phosphate buffered saline; PCR -polymerase chain reaction; TIMP-tissue inhibitor of metalloproteinase Abstract: A clear association between obesity and heart failure exists and a significant role for leptin, the product of the obese gene, has been suggested. One aspect of myocardial remodeling which characterizes heart failure is a disruption in the balance of extracellular matrix synthesis and degradation. Here we investigated the effects of leptin on matrix metalloproteinase (MMP) activity, tissue inhibitor of metalloproteinase (TIMP) expression, as well as collagen synthesis in HL-1 cardiac muscle cells. Gelatin zymographic analysis of MMP activity in conditioned media showed that leptin enhanced MMP-2 activity in a dose-and time-dependent manner. Leptin is known to stimulate phosphorylation of p38 MAPK in cardiac cells and utilization of the p38 MAPK inhibitor, SB203580, demonstrated that this kinase also plays a role in regulating several extracellular matrix components, such that inhibition of p38 MAPK signaling prevented the leptin-induced increase in MMP-2 activation. We also observed that leptin enhanced collagen synthesis determined by both proline incorporation and picrosirius red staining of conditioned media. Pro-collagen type-I and pro-collagen type-III expression, measured by real-time PCR and Western blotting were also increased by leptin, effects which were again attenuated by SB203580. In summary, these results demonstrate the potential for leptin to play a role in mediating myocardial ECM remodeling and that the p38 MAPK pathway plays an important role in mediating these effects.

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“…Multiple factors have been reported to contribute to hyperglycemia-induced cardiac damage, such as oxidative stress (3)(4)(5)(6), mitochondrial dysfunction (5)(6)(7)(8), apoptosis (5-9) and activation of several signaling molecules, including mitogen-activated protein kinase (MAPK) (3,5,10,11), leptin (6,12) and p53 (7,9). Another signaling molecule involved in hyperglycemia-induced cardiomyocyte damage may be nuclear factor-κB (NF-κB).…”

Section: Introductionmentioning

confidence: 99%

Exogenous H2S protects H9c2 cardiac cells against high glucose-induced injury and inflammation by inhibiting the activation of the NF-κB and IL-1β pathways

Chen

Lin

et al. 2014

International Journal of Molecular Medicine

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Abstract. Hyperglycemia has been reported to activate the nuclear factor-κB (NF-κB) pathway. We have previously demonstrated that exogenous hydrogen sulfide (H 2 S) protects cardiomyocytes against high glucose (HG)-induced injury by inhibiting the activity of p38 mitogen-activated protein kinase (MAPK), which can activate the NF-κB pathway and induce interleukin (IL)-1β production. In the present study, we aimed to investigate the hypothesis that exogenous H 2 S protects cardiomyocytes against HG-induced injury and inflammation through the inhibition of the NF-κB/IL-1β pathway. H9c2 cardiac cells were treated with 35 mM glucose (HG) for 24 h to establish a model of HG-induced damage. Our results demonstrated that treatment of the cells with 400 µM sodium hydrogen sulfide (NaHS, a donor of H 2 S) or 100 µM pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB) for 30 min prior to exposure to HG markedly attenuated the HG-induced increase in the expression levels of the phosphorylated (p)-NF-κB p65 subunit. Notably, pre-treatment of the H9c2 cardiac cells with NaHS or PDTC significantly suppressed the HG-induced injury, including cytotoxicity, apoptosis, oxidative stress and mitochondrial insults, as evidenced by an increase in cell viability, as well as a decrease in the number of apoptotic cells, the expression of cleaved caspase-3, the generation of reactive oxygen species (ROS) and the dissipation of mitochondrial membrane potential (MMP). In addition, pre-treatment of the cells with NaHS or PDTC ameliorated the HG-induced inflammatory response, leading to a decrease in the levels of IL-1β, IL-6 and tumor necrosis factor-α (TNF-α). Importantly, co-treatment of the H9c2 cells with 20 ng/ml IL-1 receptor antagonist (IL-1Ra) and HG markedly reduced the HG-induced increase in p-NF-κB p65 expression, cytoto xicity, the number of apoptotic cells, as well as the production of TNF-α. In conclusion, the present study presents novel mechanistic evidence that exogenous H 2 S protects H9c2 cardiac cells against HG-induced inflammation and injury, including cytotoxicity, apoptosis, overproduction of ROS and the dissipation of MMP, by inhibiting the NF-κB/IL-1β pathway. We also provide new data indicating that the positive interaction between the NF-κB pathway and IL-1β is critical in HG-induced injury and inflammation in H9c2 cardiac cells.

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Leptin and endothelin‐1 mediated increased extracellular matrix protein production and cardiomyocyte hypertrophy in diabetic heart disease

Abstract: These data indicate that in diabetes increased FN production and cardiomyocyte hypertrophy may be mediated through leptin with its interaction with ET-1.

Cited by 40 publications

References 43 publications

Endogenous Nerve Growth Factor Regulates Collagen Expression and Bladder Hypertrophy through Akt and MAPK Pathways during Cystitis

Endogenous Nerve Growth Factor Regulates Collagen Expression and Bladder Hypertrophy through Akt and MAPK Pathways during Cystitis

Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes

Exogenous H2S protects H9c2 cardiac cells against high glucose-induced injury and inflammation by inhibiting the activation of the NF-κB and IL-1β pathways

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