Statin-Sensitive Dysregulated AT1 Receptor Function and Density in Hypercholesterolemic Men

Nickenig, Georg; Bäumer, Anselm T.; Temur, Yavuz; Kebben, Daniela; Jockenhövel, F.; Böhm, Michael

doi:10.1161/01.cir.100.21.2131

Cited by 354 publications

(249 citation statements)

References 21 publications

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“…We found that the blood pressure response to noradrenaline was unchanged, which agrees with Nickenig and colleagues 4 who found no significant difference in the response to infused Figure 1 Effect of various cholesterol lowering treatments on total cholesterol and baroreflex sensitivity (BRS) in hypercholesterolaemic men. *p < 0.05 for total cholesterol and BRS.…”

Section: Resultssupporting

confidence: 90%

“…Noradrenaline was used instead of phenylephrine to test the baroreflex as it was felt to be more physiological than phenylephrine and because it had been used in a landmark study by Nickenig. 4 Supine blood pressure and heart rate were measured in triplicate at the start for baseline value and every five minutes thereafter during the study (Dinamap critical signs monitor 1846, Critikon, Tampa, Florida, USA). The infusion was stopped if the systolic blood pressure rose by 50 mm Hg.…”

Section: Methodsmentioning

confidence: 99%

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Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins?

Patterson

2002

Heart

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Section: Resultssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins?

Patterson

2002

Heart

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“…This also agrees with the finding that statin reversed the increased expression of AT1 and the augmented BP response to angiotensin II in hypercholesterolemic men. 29 Thus, it is speculated that both hypercholesterolemia and hypertension would be closely linked to augmented AT1 stimulation in this model. Although further mechanisms remain unknown, our findings imply that the combination of OLM and PRA will clinically benefit lipid and BP control per se in patients with metabolic syndrome.…”

Section: Lipid-lowering and Antihypertensive Effectsmentioning

confidence: 88%

Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model

et al. 2009

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Hypertension and dyslipidemia frequently coexist in patients with progressive insulin resistance and thus constitute metabolic syndrome. We sought to determine the merits of combining an angiotensin II receptor blocker and a 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor in treating this pathological condition. Five-week-old Otsuka Long-Evans Tokushima Fatty rats, a model of metabolic syndrome, were untreated or treated with olmesartan 3 mg kg À1 per day, pravastatin 30 mg kg À1 per day or their combination for 25 weeks. Long-Evans Tokushima Otsuka rats served as normal controls. The antihypertensive effect of olmesartan and the lipid-lowering properties of pravastatin were both augmented by the combination. The oral glucose tolerance test revealed that only the combined treatment significantly reduced the area under the time-glucose curve, which was accompanied by augmented adiponectin messenger RNA expression in epididymal adipose tissue. Although the total cardiac endothelial nitric oxide synthetase (eNOS) content did not significantly differ among the groups, the combined treatment significantly increased the content of dihydrofolate reductase, a key eNOS coupler. Dihydroethidium staining of the aorta showed that the combination most significantly attenuated superoxide production. Moreover, Azan-Mallory staining revealed that the combination most significantly limited the perivascular fibrosis and wall thickening of intramyocardial coronary arteries. In conclusion, the combination of olmesartan and pravastatin augmented adiponectin expression in white adipose tissue and improved glucose tolerance in a rat model of metabolic syndrome, which was associated with more significant ameliorations of cardiovascular redox state and remodeling than those by treatments with either agent alone.

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“…44 Statins downregulate AT1R expression in platelets and vascular smooth muscle cells. 45,46 Thus, simvastatin may prevent SAD-induced aggravation of hypertensive cardiac hypertrophy, at least in part, by inhibiting the angiotensin II-mediated mechanism. This issue should be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

et al. 2010

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Pronounced variability in blood pressure (BP) is an aggravating factor of hypertensive end-organ damage. However, its pathogenesis remains unknown. Statins have various protective effects on the cardiovascular system. Thus, we determined whether simvastatin would attenuate the aggravation of hypertensive cardiac remodeling in a rat model of hypertension with large BP variability, and also investigated the signaling mechanism involved in its effect. A model of hypertension with large BP variability was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). A SAD or sham operation was performed in 12-week-old rats. Thereafter, simvastatin (0.2 mg kg À1 per day) or vehicle was intraperitoneally administered every day. After 6 weeks , telemetric recordings revealed that SAD enhanced BP variability without changing the mean BP. SAD increased myocyte hypertrophy, myocardial fibrosis and macrophage infiltration associated with the upregulation of brain natriuretic peptide (BNP), type I procollagen, transforming growth factor (TGF)-b and monocyte chemoattractant protein (MCP)-1, and activation of RhoA, Ras and ERK1/2. Simvastatin did not change the mean BP or BP variability in SAD-operated SHRs. In SAD-operated SHRs, simvastatin attenuated myocyte hypertrophy and BNP expression, as well as RhoA, Ras and ERK1/2 activities. In contrast, simvastatin did not change myocardial fibrosis, macrophage infiltration, or the expression of procollagen and TGF-b or MCP-1 in SAD-operated SHRs. Simvastatin did not affect serum lipid levels. In conclusion, simvastatin attenuated the large BP variability-induced aggravation of cardiac hypertrophy, but not myocardial fibrosis, in SHRs. The activation of RhoA/Ras-ERK pathways may contribute to the aggravation of cardiac hypertrophy by a combination of hypertension and large BP variability.

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Statin-Sensitive Dysregulated AT1 Receptor Function and Density in Hypercholesterolemic Men

Abstract: Hypercholesterolemia induces AT1 receptor overexpression and enhances biological effects of angiotensin II in men. These findings provide novel insights into the pathogenesis of hypertension and atherosclerosis and may initiate rational and new therapeutic concepts.

Cited by 354 publications

References 21 publications

Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins?

Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins?

Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

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