Amelioration of Angiotensin II–Induced Cardiac Injury by a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor

Dechend, Ralf; Fiebeler, Anette; Park, Joon-Keun; Müller, Dominik N.; Theuer, Juergen; Mervaala, Eero; Bieringer, Markus; Gulba, Dietrich C.; Dietz, Rainer; Luft, Friedrich C.; Haller, Hermann

doi:10.1161/hc3001.092039

Cited by 142 publications

(107 citation statements)

References 37 publications

(30 reference statements)

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“…23 Furthermore, the effect of statins to reverse the elevated blood pressure response to angiotensin II infusion is accompanied by downregulated AT1 receptor density. 24,25 Angiotensin II promotes superoxide anion generation and endothelial dysfunction. 8,26 CRP upregulates AT1 receptors in vascular smooth muscle cells, and these effects are attenuated by losartan.…”

Section: Discussionmentioning

confidence: 99%

Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients

et al. 2004

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Background-Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ.Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in hypercholesterolemic, hypertensive patients. Methods and Results-This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Forty-seven hypertensive, hypercholesterolemic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 mg, or losartan 100 mg and placebo daily during each 2-month treatment period. Losartan alone or combined therapy significantly reduced blood pressure compared with simvastatin alone. Compared with losartan alone, simvastatin alone or combined therapy significantly changed lipoproteins. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and decreased plasma malondialdehyde and monocyte chemoattractant protein-1 levels relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy compared with simvastatin or losartan alone (both PϽ0.001 and Pϭ0.030 for monocyte chemoattractant protein-1 by ANOVA). Combined therapy or losartan alone significantly increased plasma adiponectin levels and insulin sensitivity (determined by QUICKI) relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (PϽ0.001 for adiponectin, Pϭ0.029 for QUICKI by ANOVA). Conclusions-Simvastatin combined with losartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy with either drug in hypercholesterolemic, hypertensive patients.

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Section: Discussionmentioning

confidence: 99%

Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients

et al. 2004

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“…Simvastatin treatment reduces NF-jB activity in both the atherosclerotic plaques and circulating mononuclear cells of diet-induced atherosclerotic animals, independently of lipid-lowering effects (43). Similarly, administration of cerivastatin significantly reduces cardiac activation of NF-jB induced by angiotensin II, without affecting cholesterol levels (29). The LDL-independent, FIG.…”

Section: Fig 7 Effects Of Statins On Nadph Oxidase In Ec Statins Smentioning

confidence: 94%

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

116

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Significance: Endothelial dysfunction and the imbalance between nitric oxide (NO) and reactive oxygen species production in the vascular endothelium are important early steps in atherogenesis, a major socioeconomic health problem. Statins have well-established roles in primary and secondary prevention of cardiovascular disease (CVD), due to both their lipid-lowering capacity and their pleiotropic properties. It is therefore important to understand the mechanisms by which statins can modify endothelial function and affect atherogenesis. Recent Advances: In the last decade, the concept of statin pleiotropy has been reinforced by a large number of cell culture, animal, and translational studies. Statins have been shown to suppress the activity of pro-oxidant enzymes (such as NADPH oxidase) and pro-inflammatory transcriptional pathways in the endothelium. At the same time, they enhance endothelial NO synthase expression and activity while they also improve its enzymatic coupling. This leads to increased NO bioavailability and improved endothelial function. Critical Issues: Despite significant recent advances, the exact mechanisms of statin pleitropy are still only partially understood. The vast majority of the published literature relies on animal studies, while the actual mechanistic studies in humans are limited. Future Directions: The success of statins as endothelium redox-modifying agents with a direct impact on clinical outcome highlights the importance of the endothelium as a therapeutic target in CVD. Better understanding of the mechanisms that underlie endothelial dysfunction could lead to the design of novel therapeutic strategies that target the vascular endothelium for the prevention and treatment of CVD. Antioxid. Redox Signal. 20, 1198Signal. 20, -1215

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“…For example, statins can function as anti-inflammatory agents, antioxidants, immunomodulators, and angiogenic agents depending on the non-transformed cell type. [131][132][133][134][135][136][137][138][139] In addition, statins can block vascular smooth muscle cell proliferation as well as signal endothelial cell survival and progenitor cell expansion. [140][141][142][143][144] These results underscore the cell type-dependent effects of statins as well as the pleiotropic effects of these agents.…”

Section: Molecular Mechanism Of Statin-induced Apoptosismentioning

confidence: 99%

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

et al. 2002

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The statin family of drugs target HMG-CoA reductase, the ratelimiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

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Amelioration of Angiotensin II–Induced Cardiac Injury by a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor

Cited by 142 publications

References 37 publications

Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients

Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

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