Rosuvastatin attenuates the elevation in blood pressure induced by overexpression of human C-reactive protein

Departments of Internal Medicine, The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Hypertension Research (Impact Factor: 2.66). 05/2011; 34(7):869-75. DOI: 10.1038/hr.2011.44
Source: PubMed


C-reactive protein (CRP) has been shown to function as an inflammatory factor to induce endothelial dysfunction and hypertension in rats. The anti-inflammatory effects of statins suggest that they may attenuate CRP-induced endothelial dysfunction and hypertension in Sprague-Dawley rats. Male Sprague-Dawley rats were injected with an adeno-associated virus (AAV) to induce overexpression of human CRP (AAV-hCRP) or green fluorescent protein (GFP) control (AAV-GFP). At 2 months after injection, rats were administered rosuvastatin by daily oral gavage (10 mg kg(-1)) for 2 additional months. Rosuvastatin administration attenuated the increased blood pressure and loss of vascular endothelial nitric oxide synthase expression in AAV-hCRP-treated rats, and N-nitro-L-arginine methyl ester blocked its hypotensive effect. Rosuvastatin also activated phosphoinositide 3-kinases/Akt, and inhibited Rho kinase activity in aorta. Rosuvastatin reduced the production of reactive oxygen species through downregulation of nicotinamide adenine dinucleotide phosphate oxidase subunits, p22 phox and gp91 phox, and upregulation of superoxide dismutase 1 expression. Rosuvastatin attenuated the increase in blood pressure in AAV-hCRP-treated rats through endothelial protection and antioxidant effects. Our data reveals a novel mechanism through which statins may lower blood pressure.

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    • "Proteins were detected by immunoblotting and visualized using enhanced chemiluminescence. Procedures were performed as described previously [22]. "
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    ABSTRACT: 20-hydroxyeicosatetraenoic acid (20-HETE) induces endothelial dysfunction and is correlated with diabetes. This study was designed to investigate the effects of 20-HETE on endothelial insulin signaling.Human umbilical vein endothelial cells (HUVECs) or C57BL/6J mice were treated with 20-HETE in the presence or absence of insulin, and p-ERK1/2, p-JNK, IRS-1/PI3K/AKT/eNOS pathway, were examined in endothelial cells and aortas by immunoblotting. eNOS activity and nitric oxide production were measured. 20-HETE increased ERK1/2 phosphorylation and IRS-1 phosphorylation at Ser616; these effects were reversed by ERK1/2 inhibition. We further observed that 20-HETE treatment resulted in impaired insulin-stimulated IRS-1 phosphorylation at Tyr632 and subsequent PI3-kinase/Akt activation. Furthermore, 20-HETE treatment blocked insulin-stimulated phosphorylation of eNOS at the stimulatory Ser1177 site, eNOS activation and NO production; these effects were reversed by inhibiting ERK1/2. Treatment of C57BL/6J mice with 20-HETE resulted in ERK1/2 activation and impaired insulin-dependent activation of the IRS-1/PI3K/Akt/eNOS pathway in the aorta. Our data suggest that the 20-HETE activation of IRS-1 phosphorylation at Ser616 is dependent on ERK1/2 and leads to impaired insulin-stimulated vasodilator effects that are mediated by the IRS-1/PI3K/AKT/eNOS pathway.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "These effects are considered to be mediated by the beneficial effects of statins on endothelial function, their interactions with the renin–angiotensin system, and their influence on large artery compliance.36,37 Some animal studies showed that rosuvastatin reduced blood pressure in spontaneously hypertensive rats and in rats with C-reactive protein (CRP)-induced endothelial dysfunction and hypertension, and these effects appeared to be related to its endothelial protection and antioxidant effects.41,42 Future randomized controlled trials are needed to investigate the blood pressure-lowering effect of rosuvastatin in patients with increased cardiovascular risk. "
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    ABSTRACT: Rosuvastatin is one of the most potent statins available for reducing circulating low-density lipoprotein cholesterol (LDL-C) levels, which enables more high-risk patients to achieve their lipid goals. Its favorable balance of effects on atherogenic and protective lipoproteins and its pleiotropic effects, including anti-inflammatory and antioxidant effects and improvement in endothelial dysfunction, are associated with slowing of progression of atherosclerosis within the artery wall and have been translated into clinical benefits for cardiovascular outcomes. This review provides an update on the safety and the efficacy of rosuvastatin in recent large clinical trials. It appears that rosuvastatin has a beneficial effect on the progression of atherosclerosis across the clinical dosage range of 2.5-40 mg. It reduced cardiovascular events in relatively low-risk subjects with elevated high-sensitivity C-reactive protein and normal low-density lipoprotein cholesterol. As with other statins, rosuvastatin did not show overall benefit in terms of survival in patients with heart failure, but certain clinical or biochemical markers reflecting underlying disease characteristics may help to identify subgroups of patients that benefit from statin therapy. In patients with end-stage renal disease undergoing chronic hemodialysis, rosuvastatin had no effect on reducing cardiovascular events. Although there is a slightly increased risk of incident diabetes with this class of agents, the absolute benefits of statin therapy on cardiovascular events overweigh the risk in patients with moderate or high cardiovascular risk or with documented cardiovascular disease. As with other statins, rosuvastatin is an appropriate therapy in addition to antihypertensive treatment to reduce cardiovascular risk in hypertensive patients.
    Preview · Article · Apr 2013 · Integrated Blood Pressure Control
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    • "However, the effects are consistent with previous findings insofar that insulin at supraphysiological concentrations increases [3H]thymidine incorporation in endothelial cells [33]. Insulin and rosuvastatin have also been shown to activate the PI3K/Akt pathway, a pathway that is well known to be involved in cell survival and proliferation [18,22,34-36]. BLX-1002 is a novel compound of the TZD family, but with no apparent PPAR affinity. "
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    ABSTRACT: The leading cause of death for patients suffering from diabetes is macrovascular disease. Endothelial dysfunction is often observed in type 2 diabetic patients and it is considered to be an important early event in the pathogenesis of atherogenesis and cardiovascular disease. Many drugs are clinically applied to treat diabetic patients. However, little is known whether these agents directly interfere with endothelial cell proliferation and apoptosis. This study therefore aimed to investigate how anti-diabetic and cardioprotective agents affect human coronary artery endothelial cells (HCAECs). The effect of anti-diabetic and cardioprotective agents on HCAEC viability, proliferation and apoptosis was studied. Viability was assessed using Trypan blue exclusion; proliferation in 5 mM and 11 mM of glucose was analyzed using [3H]thymidine incorporation. Lipoapoptosis of the cells was investigated by determining caspase-3 activity and the subsequent DNA fragmentation after incubation with the free fatty acid palmitate, mimicking diabetic lipotoxicity. Our data show that insulin, metformin, BLX-1002, and rosuvastatin improved HCAEC viability and they could also significantly increase cell proliferation in low glucose. The proliferative effect of insulin and BLX-1002 was also evident at 11 mM of glucose. In addition, insulin, metformin, BLX-1002, pioglitazone, and candesartan significantly decreased the caspase-3 activity and the subsequent DNA fragmentation evoked by palmitate, suggesting a protective effect of the drugs against lipoapoptosis. Our results suggest that the anti-diabetic and cardioprotective agents mentioned above have direct and beneficial effects on endothelial cell viability, regeneration and apoptosis. This may add yet another valuable property to their therapeutic effect, increasing their clinical utility in type 2 diabetic patients in whom endothelial dysfunction is a prominent feature that adversely affect their survival.
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