Prevention of diabetes-induced arginase activation and vascular dysfunction by Rho kinase (ROCK) knockout

Yao, Lin; Chandra, Surabhi; Toque, Haroldo A.; Bhatta, Anil; Rojas, Modesto; Caldwell, Ruth B.

doi:10.1093/cvr/cvs371

Cited by 83 publications

(80 citation statements)

References 45 publications

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“…[51][52][53][54] Several reports demonstrated that NO and Rho-kinase have opposing effects. 55,56 Rho-kinase-deficient mice revealed preserved EC function in a diabetic model. 56 Moreover, a Rho-kinase inhibitor, fasudil, significantly enhanced the 57,58 Statins upregulate eNOS by cholesterolindependent mechanisms, involving the inhibition of Rho geranyl-geranylation.…”

Section: Opposing Effects Of No and Rho-kinase In Ec Functionmentioning

confidence: 97%

“…55,56 Rho-kinase-deficient mice revealed preserved EC function in a diabetic model. 56 Moreover, a Rho-kinase inhibitor, fasudil, significantly enhanced the 57,58 Statins upregulate eNOS by cholesterolindependent mechanisms, involving the inhibition of Rho geranyl-geranylation. 59 In addition, small GTP-binding protein dissociation stimulator plays a central role in the pleiotropic effects of statins, independently of the Rho-kinase pathway.…”

Section: Opposing Effects Of No and Rho-kinase In Ec Functionmentioning

confidence: 97%

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RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

369

235

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Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system.

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Section: Opposing Effects Of No and Rho-kinase In Ec Functionmentioning

confidence: 97%

Section: Opposing Effects Of No and Rho-kinase In Ec Functionmentioning

confidence: 97%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

369

235

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“…Accordingly, arginase blockade results in improved endothelial function. 7,[11][12][13] This mechanism also seems to be highly relevant for patients with cardiovascular disease. We have shown that arginase blockade markedly improves endothelium-dependent vasodilatation in patient with coronary artery disease.…”

Section: Introductionmentioning

confidence: 99%

Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction

Kövamees

Shemyakin

Pernow

2016

Diabetes and Vascular Disease Research

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Background: Endothelial dysfunction contributes to the development of vascular complication in diabetes. Arginase has emerged as a key mechanism behind endothelial dysfunction by its reciprocal regulation of nitric oxide production by substrate competition. We hypothesized that increased arginase activity in patients with type 2 diabetes shifts the metabolism of l-arginine from nitric oxide synthase to arginase resulting in an increase in the plasma ratio of ornithine/ citrulline, and that this ratio is associated with endothelial dysfunction. Methods: Forearm endothelium-dependent vasodilatation and endothelium-independent vasodilatation were determined in 15 patients with type 2 diabetes and 10 healthy controls and related to amino acids reflecting arginase and nitric oxide synthase activity. Results: Compared to healthy controls, patients with diabetes had impaired endothelium-dependent vasodilatation and endothelium-independent vasodilatation. The ratios of ornithine/citrulline and proline/citrulline were 60% and 95% higher, respectively, in patients with diabetes than in controls (p < 0.001). The plasma ornithine/arginine ratio was 36% higher in patients with diabetes, indicating increased arginase activity. These ratios were inversely correlated to endothelium-dependent vasodilatation and endothelium-independent vasodilatation. Conclusion: Patients with diabetes and macrovascular complications have increased amino acid ratios reflecting a shift in arginine metabolism due to arginase activation. These changes are inversely related to endothelial function supporting that arginase activity contributes to endothelial dysfunction.

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“…827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 Elevated levels of peroxynitrites have been recently associated to an increased RhoA activity, largely responsible for vascular dysfunction in experimental diabetes [231]. On the same line, diabetesinduced endothelial aortic dysfunction is improved in ROCK knockout mice [232]. ROCK inhibitors such as Y-27632 and fasudil have shown promising therapeutic advantages on cardiovascular diseases including atherosclerosis, pulmonary and systemic hypertension and chronic heart failure [233,234], as well as significant beneficial effects on diabetic endothelial dysfunction of retinal [235], coronary [236] and intrarenal arteries [237].…”

Section: Rock (Rho-associated Kinase) Inhibitors -mentioning

confidence: 99%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

Nacci

Salvia

et al. 2017

Pharmacological Research

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Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

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Prevention of diabetes-induced arginase activation and vascular dysfunction by Rho kinase (ROCK) knockout

Cited by 83 publications

References 45 publications

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

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