Hypertension Associated with Reduced Plasma Thrombomodulin Levels and a Hypercoagulable State in Rats

Sawada, Kazuyoshi; Naiki, Mitsuru; Yago, Hisashi; Matsushita, Kohji; Ohtsuki, Toshiho; Kitagawa, Kazuo; Matsumoto, Masayasu; Hori, Masatsugu

doi:10.1081/ceh-120017928

Cited by 10 publications

(7 citation statements)

References 38 publications

(37 reference statements)

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“…In our study, we observed increased TAT levels after chronic Ang II infusion. Consistent with our findings, it was shown that AT 1 receptor stimulation and HTN was linked to increased activation of coagulation due to increased TF expression and thrombin generation [11–13, 16, 17], which led to a pro-thrombotic phenotype [14]. Another possible activator is the non-canonical activation of PAR-1 by matrix-metalloproteinases (MMPs) 1 or 13 [7].…”

Section: Discussionsupporting

confidence: 81%

“…Human HTN patients and animal models of HTN showed enhanced thrombin generation in plasma as measured by elevated thrombin-antithrombin (TAT) complexes [16, 17]. In addition to its important role in both hemostasis and thrombosis, thrombin can induce multiple cellular responses via activation of protease activated receptors, such as PAR-1 [7, 15].…”

Section: Introductionmentioning

confidence: 99%

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Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Antoniak

Cardenas²,

Buczek³

et al. 2016

Cardiology

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Background: Angiotensin II (Ang II) plays an important role in cardiovascular disease. It also leads to the activation of coagulation. The coagulation protease thrombin induces cellular responses by activating protease-activated receptor 1 (PAR-1). We investigated whether PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammation. Methods and Results: PAR-1^+/+ (wild-type; WT) and PAR-1^-/- mice were infused with Ang II (600 ng/kg/min) for up to 4 weeks. In WT mice, this dose of Ang II did not cause a significant increase in blood pressure but it did cause pathological changes in both the aorta and the heart. Ang II infusion resulted in vascular remodeling of the aorta, demonstrated by a significant increase in medial wall thickening and perivascular fibrosis. Importantly, both parameters were significantly attenuated by PAR-1 deficiency. Furthermore, perivascular fibrosis around coronary vessels was reduced in Ang II-treated PAR-1^-/- mice compared to WT mice. In addition, PAR-1 deficiency significantly attenuated Ang II induction of inflammatory cytokines and profibrotic genes in the aortas compared to WT mice. Finally, PAR-1 deficiency had no effect on Ang II-induced heart hypertrophy. However, the heart function measured by fractional shortening was less impaired in PAR-1^-/- mice than in WT mice. Conclusion: Our data indicate that PAR-1 plays a significant role in cardiovascular remodeling mediated by a blood pressure-independent action of Ang II.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Antoniak

Cardenas²,

Buczek³

et al. 2016

Cardiology

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“…Thrombin-antithrombin complexes levels were found previously to be elevated in SHR plasma. 10 In the present study, thrombin-antithrombin complexes levels and thrombin generation in plasma were no higher in SHR than in Wistar, suggesting a vascular bed-specific effect in the hypertension-associated prothrombotic state. Our observation of an endothelial alteration indicated by elevated circulating levels of vWF in adult SHR compared with Wistar rats leads us to consider that vascular cells could enhance thrombin generation in SHR.…”

Section: Discussionmentioning

confidence: 60%

“…[6][7][8] In spontaneously hypertensive rats (SHR), in deoxycorticosterone acetate-induced hypertensive rats, and in endothelial dysfunction-induced experimental hypertension, a hypercoagulable state was demonstrated by elevated levels of thrombin-antithrombin complexes, as well as d-dimers, and supported by an increase in TF 9 and a decrease in thrombomodulin. 10 In experimental models of hypertension, the direct contribution of vascular cells to thrombin generation is not well documented. Early works focused primarily on the increased vascular expression of TF and antifibrinolytic molecules.…”

mentioning

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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“…An elevated fibrin monomer polymerization rate is associated with ischemic cerebrovascular disease and is an independent risk factor for this disease (24). Sawada et al reported that the plasma levels of thrombomodulin, which is localized to endothelial cells as a receptor of thrombin, decreased due to endothelial injury in deoxycorticosteron acetate-treated hypertensive rats (25). In addition, the blood prothrombin time was significantly shorter in SHR than WKY (26).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of the Coagulation System in Spontaneously Hypertensive and Hyperlipidemic Rats

Amagasa

Okazaki

Iwai

et al. 2005

JAT

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As a risk factor for cardiovascular and cerebrovascular disease, hypertension and hyperlipidemia are believed to provoke vascular damage leading to a hypercoagulative state. The aim of the present study was to investigate the coagulative and fibrinolytic activity and hepatic mRNA expression of the coagulative factors in spontaneously hypertensive and hyperlipidemic female rats (SHHR: > 150 mmHg of systolic blood pressure, > 150 mg/dl of plasma cholesterol). Plasma levels of fibrinogen, thrombinantithrombin III (ATIII) complexes and ATIII in the SHHR at 9 months of age increased significantly compared with those of age-matched Sprague-Dawley rats (SD). In the SHHR, the hepatic mRNA expression of the α α α α α-and β β β β β-chains, but not the γ γ γ γ γ-chain of fibrinogen and prothrombin was significantly enhanced. Therefore, the hyperfibrinogenemia in the SHHR was demonstrated to be due to the increase in hepatic mRNA expression of α α α α α-and β β β β β-chains of fibrinogen. The pathological findings of the aortic arch from the 9-month old SHHR were cytoplasmic vacuolization and intimal thickening in the endothelium. These results suggest that hypercoagulation concomitant with the increase in hepatic mRNA expression of fibrinogen components may contribute to the development of atherosclerosis in the SHHR. J Atheroscler Thromb, 2005; 12: 191-198.

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Hypertension Associated with Reduced Plasma Thrombomodulin Levels and a Hypercoagulable State in Rats

Cited by 10 publications

References 38 publications

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

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

Enhancement of the Coagulation System in Spontaneously Hypertensive and Hyperlipidemic Rats

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