Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats

Lin, Guorong; Craig, Graham P.; Zhang, Lili; Yuen, Violet G.; Allard, Michael F.; McNeill, John H.; MacLeod, Kathleen M.

doi:10.1016/j.cardiores.2007.03.009

Cited by 75 publications

(69 citation statements)

References 38 publications

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“…We hypothesized that the Rho/ROCK signaling pathway may be involved in the increase in visfatin and type I procollagen levels, since previous studies have shown a role for this pathway in chronic fibrosis of the liver and kidney (19,25), and that it is activated in the heart of diabetic rats (21,22). The present study showed that high-glucose treatment increased the expression levels of ROCK1, visfatin and type I procollagen in CFs from newborn rats.…”

Section: Discussionsupporting

confidence: 55%

“…The Rho/ROCK signaling pathway is implicated in chronic fibrosis of the liver and kidneys (19,20). Previous studies showed that the ROCK pathway is also activated in the cardiac cells of rats with diabetes (21,22). The expression of the Ras homolog gene family, member A (RhoA) protein was upregulated and its activity was enhanced, resulting in increased polymerization of the actin cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

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High glucose induces Rho/ROCK-dependent visfatin and typeï¿½I procollagen expressionï¿½inï¿½rat primaryï¿½cardiac fibroblasts

et al. 2014

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Abstract. Myocardial fibrosis and excessive proliferation of cardiac fibroblasts (CFs) contribute to diabetic cardiomyopathy (DCM). However, the underlying mechanism is still not completely clear. The aim of this study was to investigate the relationship between high-glucose treatment and the expression of visfatin and type I procollagen in rat CFs, and examine the regulatory effects of high-glucose treatment on the Rho/ROCK signaling pathway. CFs from newborn Sprague Dawley rats were treated with high concentrations of glucose (10, 30 and 50 mmol/l D-glucose), a baseline concentration of glucose (5.5 mmol/l) as a control, and mannitol (5.5 mmol/l D-glucose + 44.5 mmol/l mannitol) as an osmotic control. CFs were also treated with 30 mmol/l D-glucose for 6, 12, 24 and 48 h. The proliferation of CFs was determined by the MTT assay. The mRNA and protein expression of visfatin and type I procollagen were quantified by RT-qPCR and western blot analysis, respectively. Cardiac fibroblast proliferation reached a peak at 30 mmol/l D-glucose, and visfatin and type I procollagen expression were significantly increased upon treatment with high concentrations of glucose (10 and 30 mmol/l) compared to baseline glucose treatment. Treatment with 30 mmol/l D-glucose time-dependently promoted cardiac fibroblast proliferation. The mRNA and protein expression of visfatin and type I procollagen were significantly increased compared to the control at 24 h after 30 mmol/l D-glucose treatment. Y27632, a Rho-associated protein kinase (ROCK) inhibitor, significantly decreased the mRNA and protein levels of visfatin and type I procollagen, induced by 30 mmol/l D-glucose (all P<0.05). In conclusion, a high level of glucose promotes cardiac fibroblast proliferation, and induces visfatin and type I procollagen expression in CFs, at least partially via the Rho/ROCK signaling pathway. These results may be helpful in developing an appropriate therapeutic strategy for DCM.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

High glucose induces Rho/ROCK-dependent visfatin and typeï¿½I procollagen expressionï¿½inï¿½rat primaryï¿½cardiac fibroblasts

et al. 2014

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“…ROCK regulates not only the actin cytoskeleton but also the expression of genes associated with tissue fibrosis [10,34] . Data from some studies [35,36] suggest diabetes impairs cardiac function through upregulation of RhoA. The increase in RhoA expression and activity in diabetic hearts resulted in increased phosphorylation of ROCK targets, LIM kinase and ezrin/radixin/moesin, leading to an increase in actin polymerization which might be associated with cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Zhou

Wang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts. Methods: A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rhokinase inhibitor fasudil hydrochloride hydrate (10 mg·kg -1 ·d -1 , ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting. Results: In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved. Conclusion: The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

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“…Two isoforms of ROCK, ROCK1 and ROCK2, have been identified, and both are widely expressed (38). Overactivation of the RhoA-ROCK pathway has been implicated in the development of many forms of cardiovascular disease, including hypertension, heart failure, and diabetic cardiomyopathy (26). Increased ROCK activity has also been detected in the heart and other tissues from obese, insulin-resistant animal models (25) and in leukocytes from patients with metabolic syndrome (27).…”

mentioning

confidence: 99%

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Soliman

Nyamandi

Garcia-Patino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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KM. Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction. Am J Physiol Heart Circ Physiol 309: H70 -H81, 2015. First published April 24, 2015 doi:10.1152/ajpheart.00664.2014.-Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2 ϩ/Ϫ mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2 ϩ/Ϫ mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr 612 , Akt, and AS160 was also impaired in these hearts, while Ser 307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2 ϩ/Ϫ mice, and cardiac levels of TNF␣ were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesityinduced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition. ROCK2; insulin signaling; heart; insulin receptor substrate phosphorylation

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Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats

Cited by 75 publications

References 38 publications

High glucose induces Rho/ROCK-dependent visfatin and typeï¿½I procollagen expressionï¿½inï¿½rat primaryï¿½cardiac fibroblasts

High glucose induces Rho/ROCK-dependent visfatin and typeï¿½I procollagen expressionï¿½inï¿½rat primaryï¿½cardiac fibroblasts

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

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