Rho kinase and protein kinase C involvement in vascular smooth muscle myofilament calcium sensitization in arteries from diabetic rats

Kizub, Igor V.; Pavlova, Oleksandra O.; Johnson, Christopher D.; Soloviev, Anatoly I.; Zholos, Alexander

doi:10.1111/j.1476-5381.2010.00666.x

Cited by 47 publications

(42 citation statements)

References 48 publications

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“…In the case of type 1 diabetes, dysfunction of endothelial cells plays a key role in the pathogenic disorder of vasculature. The upregulation of ROCK and the reduction of the endothelial NO production are closely associated by the involvement of RhoA/ROCK signaling pathway, while suppressing ROCK activity restores vascular function (Cicek et al 2013;El-Remessy et al 2010;Kizub et al 2010;Yao et al 2013). In the present study, majority of endothelial cell layers were tightly adhered to the elastin layer in the presence of Y-27632, and PECAM expression was also maintained at a level similar to that of the fresh mesenteric artery (Figure 3).…”

Section: Discussionsupporting

confidence: 64%

ROCK inhibitor, Y-27632, reduces FBS-induced structural alteration in organ-cultured mesenteric artery

2013

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Background: Chronic treatment with fetal bovine serum (FBS) causes gradual vasoconstriction, vascular wall thickening, and contractility reduction in organ-cultured vascular tissues. We have previously demonstrated that Rho-associated kinase (ROCK) inhibitors prevent the functional alterations of small arteries in response to the FBS treatment. Here, we tested a further hypothesis that the chronic inhibition of ROCK has a protective effect on FBS-induced structural alterations. Methods: To verify the new hypothesis, the rabbit mesenteric arterial rings were cultured in FBS-supplemented culture medium with or without Y-27632, a reversible ROCK inhibitor and then western blot, immunohistochemistry, apoptosis assay, and electron microscopy were performed using organ-cultured arterial rings.

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Section: Discussionsupporting

confidence: 64%

ROCK inhibitor, Y-27632, reduces FBS-induced structural alteration in organ-cultured mesenteric artery

2013

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“…Similar effects have been observed in detrusor and airway smooth muscle, suggesting a general mechanism for some smooth muscle tissues (44,45). In many cases, the cause of glucose-induced smooth muscle hypercontractility has been ascribed to an increased PKC/Rho-kinase activity (10,13,14,43,45,46). Increasing levels of glucose cause an elevation in cytosolic calcium levels in vascular smooth muscle (10,47), and both PKC and Rho activation are in part dependent on intracellular calcium levels (48,49).…”

Section: Discussionmentioning

confidence: 71%

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Hien¹,

Turczyńska²,

Dahan³

et al. 2016

Journal of Biological Chemistry

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Both type 1 and type 2 diabetes are associated with increased risk of cardiovascular disease. This is in part attributed to the effects of hyperglycemia on vascular endothelial and smooth muscle cells, but the underlying mechanisms are not fully understood. In diabetic animal models, hyperglycemia results in hypercontractility of vascular smooth muscle possibly due to increased activation of Rho-kinase. The aim of the present study was to investigate the regulation of contractile smooth muscle markers by glucose and to determine the signaling pathways that are activated by hyperglycemia in smooth muscle cells. Microarray, quantitative PCR, and Western blot analyses revealed that both mRNA and protein expression of contractile smooth muscle markers were increased in isolated smooth muscle cells cultured under high compared with low glucose conditions. This effect was also observed in hyperglycemic Akita mice and in diabetic patients. Elevated glucose activated the protein kinase C and Rho/Rho-kinase signaling pathways and stimulated actin polymerization. Glucose-induced expression of contractile smooth muscle markers in cultured cells could be partially or completely repressed by inhibitors of advanced glycation end products, L-type calcium channels, protein kinase C, Rho-kinase, actin polymerization, and myocardin-related transcription factors. Furthermore, genetic ablation of the miR-143/145 cluster prevented the effects of glucose on smooth muscle marker expression. In conclusion, these data demonstrate a possible link between hyperglycemia and vascular disease states associated with smooth muscle contractility.Diabetes confers a 2-4-fold excess risk for a wide range of cardiovascular diseases, including macrovascular complications leading to coronary heart disease and ischemic stroke, as well as microvascular diseases, such as nephropathy and retinopathy (1, 2). Based on current trends, the rising incidence of diabetes (expected to reach 333 million people worldwide by 2025) will undoubtedly equate to increased cardiovascular mortality. Chronic hyperglycemia has long been recognized as an independent risk factor for cardiovascular disease (3, 4). Importantly, the progressive relationship between glucose levels and cardiovascular risk extends below the threshold for diabetes diagnosis (fasting plasma glucose Ն7.0 mmol/liter or 2-h plasma glucose Ն11.1 mmol/liter (2, 3)), and more recently, even transient hyper-and hypoglycemia have emerged as important determinants of cardiovascular disease (5). Despite the vast clinical and epidemiological experience linking blood glucose and poor glucose control to the development and progression of cardiovascular disease, the underlying molecular mechanisms leading to vascular dysfunction and disease are poorly understood (6).It has been well established that hyperglycemia results in vascular hyperreactivity in diabetic patients (7) and animal models (8 -10). Part of this effect may be attributed to a decrease in nitric oxide (NO) bioavailability as well as a reduced respon...

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“…Growing experimental evidence demonstrates that increased smooth muscle Ca 2ϩ sensitivity mediated by RhoK plays a main role in the augmented vasoconstriction of the diabetic vasculature (15,23,26,46). Concerning erectile tissue, enhanced activity of the RhoA/RhoK pathway has been demonstrated to be involved in the impaired erectile function of rodent models of both type 1 diabetes (7) and metabolic syndrome (44,46).…”

Section: Discussionmentioning

confidence: 99%

“…Both augmented smooth muscle contractility and endothelial dysfunction have been shown to underlie the abnormal vasoconstriction in arteries from diabetic and metabolic syndrome patients and animal models (16,18,19,28). The enhanced vascular smooth muscle contractile responses in diabetes have, in turn, been ascribed to increases in Ca 2ϩ entry and/or Ca 2ϩ release (1,6,16,36), although elevation in the Ca 2ϩ sensitivity of the contractile proteins has alternatively been proposed as the mechanism underlying the increased vascular contractility associated with diabetes (12,23,26).…”

mentioning

confidence: 99%

Impaired Ca²⁺ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

Villalba

Contreras

Hernández

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Diabetes is associated with an increased vascular tone usually involved in the pathogenesis of diabetic cardiovascular complications such as hypertension, stroke, coronary artery disease, or erectile dysfunction (ED). Enhanced contractility of penile erectile tissue has been associated with augmented activity of the RhoA/Rho kinase (RhoK) pathway in models of diabetes-associated ED. The present study assessed whether abnormal vasoconstriction in penile arteries from prediabetic obese Zucker rats (OZRs) is due to changes in the intracellular Ca2+ concentration ([Ca2+]i) and/or in myofilament Ca2+ sensitivity. Penile arteries from OZRs and lean Zucker rats (LZRs) were mounted on microvascular myographs for simultaneous measurements of [Ca2+]i and tension. The relationships between [Ca2+]i and contraction for the α1-adrenergic vasoconstrictor phenylephrine (PE) were left shifted and steeper in OZRs compared with LZRs, although the magnitude of the contraction was similar in both groups. In contrast, the vasoconstriction induced by the thromboxane A2 receptor agonist U-46619 was augmented in arteries from OZRs, and this increase was associated with an increase in both the sensitivity and maximum responses to Ca2+. The RhoK inhibitor Y-27632 (10 μM) reduced the vasoconstriction induced by PE to a greater extent in OZRs than in LZRs, without altering Ca2+. Y-27632 inhibited with a greater potency the contraction elicited by high KCl in arteries from OZRs compared with LZRs without changing [Ca2+]i. RhoK-II expression was augmented in arteries from OZRs. These results suggest receptor-specific changes in the Ca2+ handling of penile arteries under conditions of metabolic syndrome. Whereas augmented vasoconstriction upon activation of the thromboxane A2 receptor is coupled to enhanced Ca2+ entry, a RhoK-mediated enhancement of myofilament Ca2+ sensitivity is coupled with the α1-adrenergic vasoconstriction in penile arteries from OZRs.

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Rho kinase and protein kinase C involvement in vascular smooth muscle myofilament calcium sensitization in arteries from diabetic rats

Cited by 47 publications

References 48 publications

ROCK inhibitor, Y-27632, reduces FBS-induced structural alteration in organ-cultured mesenteric artery

ROCK inhibitor, Y-27632, reduces FBS-induced structural alteration in organ-cultured mesenteric artery

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Impaired Ca²⁺ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

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Rho kinase and protein kinase C involvement in vascular smooth muscle myofilament calcium sensitization in arteries from diabetic rats

Cited by 47 publications

References 48 publications

ROCK inhibitor, Y-27632, reduces FBS-induced structural alteration in organ-cultured mesenteric artery

ROCK inhibitor, Y-27632, reduces FBS-induced structural alteration in organ-cultured mesenteric artery

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Impaired Ca2+ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

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Impaired Ca²⁺ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase