Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Rouf R
PROVIDER: S-EPMC5543913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transforming growth factor-? (TGF?) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGF? can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal-regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGF?. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase-1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGF? signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.
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Project description:Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or ?-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and ?1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.
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Project description:We hope to determine the importance of different genes (including B receptors) in anthracycline-induced cardiomyopathy. This has important benefits to patients exposed to anthracyclines, as this could help determine whether certain individuals have increased susceptibility to cardiac injury.
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Project description:Matrix metalloproteinases (MMPs) play a pivotal role in tissue remodeling by degrading the extracellular matrix (ECM) components. This mechanism is implicated in a variety of physiological and pathological cellular processes including wound healing. One of the key proteins involved in this process is the proinflammatory cytokine interleukin-1? (IL-1?, which induces the expression of MMP-3 mRNA and the secretion of MMP-3 protein by dermal fibroblasts. In this study, we first investigated the contribution of activating transcription factor 2 (ATF-2) to IL-1?-induced MMP-3 expression in dermal fibroblasts. Our results showed that in cells transfected with ATF-2 siRNA or treated with the ATF-2 inhibitor SBI-0087702, IL-1?-induced MMP-3 mRNA expression was reduced. We also demonstrated that IL-1? stimulates the phosphorylation of ATF-2. These observations suggest that ATF-2 plays an important role in IL-1?-induced MMP-3 expression. Next, we investigated the role of MAPK signaling in ATF-2 activation. In cells treated with the extracellular signal-regulated kinase (ERK) inhibitor FR180240, as well as in cells transfected with ERK1 and ERK2 siRNAs, IL-1?-induced MMP-3 mRNA expression was reduced. In addition, we showed that IL-1? induced the phosphorylation of ERK1/2. These observations suggest that ERK1 and ERK2 are involved in IL-1?-induced MMP-3 expression. However, ERK1 and ERK2 do seem to play different roles. While the ERK inhibitor FR180204 inhibited IL-1?-induced ATF-2 phosphorylation, only in cells transfected with ERK1 siRNA, but not ERK2 siRNA, IL-1?-induced ATF-2 phosphorylation was reduced. These findings suggest that the ERK1/ATF-2 signaling axis contributes to IL-1?-induced MMP-3 expression in dermal fibroblasts.
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Project description:Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5'-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the Lieber-DeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5'-nucleotidase or adenosine A1 or A2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A1 or A2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A2B receptors. In vitro studies supported roles for adenosine A1 receptors in promoting fatty acid synthesis and for A2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A1 and A2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver.
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Project description:Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in the fibrillin-1 gene. Pulmonary functional abnormalities, such as emphysema and restrictive lung diseases, are frequently observed in patients with MFS. However, the pathogenesis and molecular mechanism of pulmonary involvement in MFS patients are underexplored. Notch signaling is essential for lung development and the airway epithelium regeneration and repair. Therefore, we investigated whether Notch3 signaling plays a role in pulmonary emphysema in MFS. By using a murine model of MFS, fibrillin-1 hypomorphic mgR mice, we found pulmonary emphysematous-appearing alveolar patterns in the lungs of mgR mice. The septation in terminal alveoli of lungs in mgR mice was reduced compared to wild type controls in the early lung development. These changes were associated with increased Notch3 activation. To confirm that the increased Notch3 signaling in mgR mice was responsible for structure alterations in the lungs, mice were treated with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglucine t-butyl ester (DAPT), a ?-secretase inhibitor, which inhibits Notch signaling. DAPT treatment reduced lung cell apoptosis and attenuated pulmonary alteration in mice with MFS. This study indicates that Notch3 signaling contributes to pulmonary emphysema in mgR mice. Our results may have the potential to lead to novel strategies to prevent and treat pulmonary manifestations in patients with MFS.
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Project description:The extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is activated by several growth factors and mitogens, and upregulation has been noted in many human cancers, including examples in the lung. In this study, to study the association of ERK1/2 activation with mutation of Kras encoding an upstream activator of ERK1/2 in lung premalignant lesions, we immunohistochemically examined expression of phosphorylated forms of ERK1/2 (pERK1/2) and MAP/ERK kinase 1/2 (pMEK1/2) proteins and correlation between ERK activation and mutation of Kras encoding an upstream activator of ERK1/2, in a mouse lung carcinogenesis model. Female 7-week-old A/J mice were administered a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), then maintained without additional treatment until sacrifice at week 52. Histopathologically, adenocarcinomas, adenomas and hyperplasias were observed in the lung. pMEK1/2 was expressed mostly in the cell cytoplasm in all three. In contrast, pERK1/2-positive cells were also relatively rare in any histological types as compared with level of pMEK1/2 expression. However, pERK1/2-positive cells in adenocarcinoma were still markedly more common than in hyperplasias and adenomas (~5-fold, ~4-fold; P < 0.01). Activating mutations of Kras gene at codons 12, 13 and 61 were detected in the majority of adenomas and adenocarcinomas, but without any significant relation to pERK1/2 expression. These results suggest that activation of ERK1/2 plays a key role in malignant transformation during lung carcinogenesis featuring Kras mutaion. Activation of ERK1/2 in lung premalignant lesions was little regardless of the mutation of Kras, and ERK1/2 activation in NNK-induced mouse lung carcinogenesis may be regulated not only by Kras mutation but also other signaling pathway or regulatory factor.
| S-EPMC4864820 | biostudies-other
Project description:RATIONALE:Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complications of Marfan syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor-beta (TGF-?) and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS, Fbn1(mgR/mgR). Losartan has been shown to prevent aneurysms in another mouse model of MFS, Fbn1(C1039G/+), through inhibition of the Erk1/2 pathway. However, the role of MMP-2 in MFS and effect of losartan on the lifespan of MFS mice remain unknown. OBJECTIVE:We investigated the role of MMP-2 in MFS and compared the effects of losartan and doxycycline on aortic dilatation and survival in Fbn1(mgR/mgR) mice. METHODS AND RESULTS:By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1(mgR/mgR) mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression, whereas both drugs decreased Erk1/2 phosphorylation. When combined, only one of nine mice died within the 30-week study; aortic histology and diameter were normalized and the effects on Smad2 phosphorylation was additive. To further explore the role of MMP-2 in MFS, we created MMP-2-deficient Fbn1(mgR/mgR) mice. MMP-2 deletion inhibited activation of TGF-? and phosphorylation of Erk1/2 and Smad2 and prolonged the lifespan of the mice. CONCLUSIONS:These studies demonstrated that inhibition of MMP-2 by doxycycline delayed the manifestations of MFS, in part, through its ability to decrease active TGF-? and the noncanonical signaling cascade downstream of TGF-?. This study further suggested that targeting TGF-? signaling at different points might be a more effective strategy for inhibiting disease progression.
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Project description:Stroke is an acute cerebro-vascular disease with high incidence and poor prognosis, most commonly ischemic in nature. In recent years, increasing attention has been paid to inflammatory reactions as symptoms of a stroke. However, the role of inflammation in stroke and its underlying mechanisms require exploration. In this study, we evaluated the inflammatory reactions induced by acute ischemia and found that pyroptosis occurred after acute ischemia both in vivo and in vitro, as determined by interleukin-1β, apoptosis-associated speck-like protein, and caspase-1. The early inflammation resulted in irreversible ischemic injury, indicating that it deserves thorough investigation. Meanwhile, acute ischemia decreased the Sirtuin 1 (Sirt1) protein levels, and increased the TRAF6 (TNF receptor associated factor 6) protein and reactive oxygen species (ROS) levels. In further exploration, both Sirt1 suppression and TRAF6 activation were found to contribute to this pyroptosis. Reduced Sirt1 levels were responsible for the production of ROS and increased TRAF6 protein levels after ischemic exposure. Moreover, N-acetyl-L-cysteine, an ROS scavenger, suppressed the TRAF6 accumulation induced by oxygen-glucose deprivation via suppression of ROS bursts. These phenomena indicate that Sirt1 is upstream of ROS, and ROS bursts result in increased TRAF6 levels. Further, the activation of Sirt1 during the period of ischemia reduced ischemia-induced injury after 72 h of reperfusion in mice with middle cerebral artery occlusion. In sum, these results indicate that pyroptosis-dependent machinery contributes to the neural injury during acute ischemia via the Sirt1-ROS-TRAF6 signaling pathway. We propose that inflammatory reactions occur soon after oxidative stress and are detrimental to neuronal survival; this provides a promising therapeutic target against ischemic injuries such as a stroke.
| S-EPMC7410906 | biostudies-literature
Project description:Doxorubicin (DOX) is an effective anticancer agent. Its clinical use is, however, limited due to its detrimental side effects, especially the cardiotoxicity caused by ROS, mitochondrial dysfunction and apoptosis. 3',4'-dihydroxyflavonol (DiOHF) is a recently developed potent synthetic flavonoid which has been reported to exert anti-oxidative activity in myocardial ischemia-reperfusion injury and maintain the normal mitochondrial function. The aim of this study was to explore the protective effects of DiOHF on the DOX-induced cardiotoxicity. We established DOX-induced cardiotoxicity in H9C2 cells by incubation with 1 ?M DOX and in BALB/c mice by DOX injection. DiOHF effectively prevented and reversed the DOX-induced cardiotoxicity, including ROS production, mitochondrial dysfunction, and apoptosis. The DOX-induced cardiotoxicity was accompanied by ERK1/2 activation and abolished by the silence of ERK1, rather than ERK2. Furthermore, DOX treatment in mice induced an increase in serum CK-MB level and myocardial fibrosis with a reduction in left ventricular (LV) function. These detrimental effects were blunted by DiOHF administration. Conclusion: DiOHF suppresses and reverses the DOX-induced cardiotoxicity by inhibiting ROS release, stabilizing mitochondrial function and reducing apoptosis through activation of the ERK1 signaling.
| S-EPMC6777440 | biostudies-literature