A novel function of FoxO transcription factors in thrombin-stimulated vascular smooth muscle cell proliferation

Mahajan, Shailaja G.; Fender, Anke C.; Meyer-Kirchrath, Jutta; Kurt, Muhammed; Barth, Mareike; Sagban, Tolga Atilla; Fischer, Jens W.; Schrör, Karsten; Hohlfeld, Thomas; Rauch, Bernhard

doi:10.1160/th11-11-0756

Cited by 27 publications

(25 citation statements)

References 48 publications

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“…Our data indicate that the mechanism involves increased PAR-1 expression and Akt signaling pathway activation as previously reported. 30 Thrombus formation in large arteries starts by plateletplatelet cross-linking involving GPIIbIIIa receptors and GPIbα-vWF interactions, followed by formation of a fibrin network to anchor the platelet-rich thrombus to the vessel wall. 31 Fibrin formation is dependent on the exposure of procoagulant material on the SMC surface at the site of vascular injury.…”

Section: Discussionmentioning

confidence: 99%

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Ait‐Aissa

Lagrange

Mohamadi

et al. 2015

ATVB

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Objective-The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. Approach and Results-We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12-but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl 3 -induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. Conclusions-The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors. Ait Aissa et al Thrombin Generation in SHR Arteries 931One concern is that the function of the complex thrombin generation process is difficult to assess from estimates of its separate contributing elements. It would be preferable to estimate the overall activity of the hemostatic and thrombotic system and its relation with vascular function. This can be attempted by using a global in vitro test, such as the calibrated automated thrombogram, designed to explore the thrombin generation process under conditions as close as possible to those in vivo. This test has been shown to indicate a thrombotic tendency in several clinical settings, 11-14 which seems to be an independent predictor of acute ischemic stroke. 15The present study tests, in SHR, the hypothesis that changes in coagulation proteins and membrane phospholipid organization cause an increased thrombin-generating capacity within the vascular wall because SMC phenotypic modulation is a hallmark of hypertension. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Hypertension-Associated Changes in Circulating Endothelial MarkersThe weight of SHR rats was significantly lower compared with the age-matched Wistar rats (94±5 versus 141±2 g at 5 weeks of age and 335±5...

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Section: Discussionmentioning

confidence: 99%

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Ait‐Aissa

Lagrange

Mohamadi

et al. 2015

ATVB

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“…As in endothelial cells, thrombin induces apoptosis and expression of MMPs in smooth muscle cells. These processes reportedly affect the structure of blood vessels in a manner that promotes atherosclerosis [39][40][41][42][43]. In atherosclerotic lesions, PAR1 expression is increased [1].…”

Section: Blood Vesselsmentioning

confidence: 99%

Bidirectional Pathologic Effects of Thrombin

Hidai¹

2018

Anat Physiol

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Hemostasis is an essential reaction in organisms with circulatory systems. To stop bleeding as soon as possible, reactions of the coagulation system proceed rapidly and are regulated by positive feedback loops. However, coagulation can be harmful when induced at inappropriate sites, potentially resulting in local thromboembolisms in vital organs such as the heart and brain and systemic microthrombi in conditions such as disseminated intravascular coagulopathy. Increasingly, reports indicate that coagulation-related factors can cause serious diseases without obvious thromboembolism-associated ischemia, for example, atherosclerosis and Alzheimer disease. Thrombin is an essential coagulation factor that can also cause tissue injury, particular to endothelial cells. However, thrombin can also function as a tissue-protective factor depending on conditions. Endothelial protein C receptor (EPCR) and protease-activated receptors (PARs) regulate thrombin activity, but many details regarding the mechanisms remain unknown. This short review summarizes the bidirectional effects of thrombin signaling via EPCR and PAR1 and discusses points relevant to translating the tissue-protective effects of thrombin into clinical benefits.

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“…Akt can block apoptosis by phosphorylating FoxO proteins, promoting the sequestration of FoxO proteins by 14-3-3 in the cytoplasm, and ultimately blocking their transcription [53, 78, 93]. Once forkhead transcription factor activity is inhibited, Aβ toxicity can be limited [92, 94], vascular survival is enhanced during experimental diabetes [95, 96], erythroid progenitors differentiation is promoted [97], smooth muscle proliferation is enhanced [98], and the detrimental effects of neonatal hypoxia-ischemic encephalopathy may be reduced [99]. However, it is important to note that forkhead transcription factor blockade also may be detrimental during unchecked tumor growth such as in gastric cancer [100] and lymphoma [101].…”

Section: Wisp1 Signalingmentioning

confidence: 99%

WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

Maiese¹

2014

CNR

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As a proliferative and restorative entity, Wnt1 inducible signaling pathway protein 1 (WISP1) is emerging as a novel target for a number of therapeutic strategies that are relevant for disorders such as traumatic injury, neurodegeneration, musculoskeletal disorders, cardiovascular disease, pulmonary compromise, and control of tumor growth as well as distant metastases. WISP1, a target of the wingless pathway Wnt1, oversees cellular mechanisms that include apoptosis, autophagy, cellular migration, stem cell proliferation, angiogenesis, immune cell modulation, and tumorigenesis. The signal transduction pathways of WISP1 are broad and involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), mitogen activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK), caspases, forkhead transcription factors, sirtuins, c-myc, glycogen synthase kinase -3β (GSK-3β), β-catenin, miRNAs, and the mechanistic target of rapamaycin (mTOR). Ultimately, these signal transduction pathways of WISP1 can result in varied and sometimes unpredictable outcomes especially for cell survival, tissue repair, and tumorigenesis that demand increased insight into the critical role WISP1 holds for cellular biology and clinical medicine.

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A novel function of FoxO transcription factors in thrombin-stimulated vascular smooth muscle cell proliferation

Cited by 27 publications

References 48 publications

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Bidirectional Pathologic Effects of Thrombin

WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

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