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(Circulation. 2001;104:576.)
© 2001 American Heart Association, Inc.

Basic Science Reports

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

Ralf Dechend, MD; Anette Fiebeler, MD; Joon-Keun Park, PhD; Dominik N. Muller, PhD; Juergen Theuer, MD; Eero Mervaala, MD; Markus Bieringer, MS; Dietrich Gulba, MD; Rainer Dietz, MD; Friedrich C. Luft, MD, FRCP (Edin); Hermann Haller, MD

From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin (R.D., D.N.M., J.T., E.M., M.B., D.G., R.D., F.C.L.), Berlin, Germany, and Nephrology Division, Department of Medicine, Hannover Medical School (A.F., J.-K.P., H.H.), Hannover, Germany.

Correspondence to Friedrich C. Luft, MD, Charité Campus-Buch, Franz Volhard Clinic, Wiltberg Str 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de

	Abstract

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Background— 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects that extend beyond cholesterol reduction. We used an angiotensin (Ang) II–dependent model to test the hypothesis that cerivastatin ameliorates cardiac injury.

Methods and Results— We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from weeks 4 to 7 with cerivastatin (0.5 mg/kg by gavage). We used immunohistochemistry, electrophoretic mobility shift assays, and reverse transcription–polymerase chain reaction techniques. Compared with control dTGR, dTGR treated with cerivastatin had reduced mortality, blood pressure, cardiac hypertrophy, macrophage infiltration, and collagen I, laminin, and fibronectin deposition. Basic fibroblast growth factor mRNA and protein expression were markedly reduced, as was interleukin-6 expression. The transcription factors NF-B and AP-1 were substantially less activated, although plasma cholesterol was not decreased.

Conclusions— These results suggest that statins ameliorate Ang II–induced hypertension, cardiac hypertrophy, fibrosis, and remodeling independently of cholesterol reduction. Although the clinical significance remains uncertain, the results suggest that statins interfere with Ang II–induced signaling and transcription factor activation, thereby ameliorating end-organ damage.

Key Words: statins • angiotensin • remodeling • cholesterol

	Introduction

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Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are effective in preventing acute coronary events; however, careful analysis suggests that the benefits of statins cannot be fully explained on the basis of cholesterol reduction alone. Clinical and laboratory observations have shown an inhibition of vascular smooth muscle cell (VSMC) proliferation by statins that is independent of LDL cholesterol levels. Such an effect might be expected, because inhibition of isoprenoid formation, precursors of sterol synthesis, is important in altering the processing of signaling proteins that require lipidation, such as Ras.¹ In a patient study, Nickenig et al² recently showed that statin treatment effectively reduced angiotensin (Ang) II type 1 (AT1) receptor density and decreased the blood pressure-elevating effects of Ang II. They suggested that this effect might explain some of the cholesterol-independent statin effects. We have studied a double transgenic rat (dTGR) model of Ang II–induced end-organ damage.³ The rats harbor the human renin and angiotensinogen genes. dTGR display severe cardiac and renal inflammatory injury and die at 7 weeks of age if untreated. We used this model to test the hypothesis that HMG Co-A reductase inhibition might exert cholesterol-independent protective effects on the heart.

	Methods

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Study Design
Experiments were conducted in 4-week-old male dTGR and age-matched Sprague-Dawley (SD) rats. The dTGR line and characteristics were described elsewhere.⁴ All procedures were done according to guidelines from the American Physiological Society and were approved by local authorities. The statin dTGR group (n=15) received cerivastatin for 3 weeks by gavage once a day (0.5 mg/kg). Control dTGR (n=20) and SD rats (n=15) received vehicle. This dose, on a weight basis, is much higher than the human dose, although the pharmacokinetic area under the curve and peak plasma levels are similar in both species.⁵ Statins do not lower serum cholesterol in rats because of compensatory increases in hepatic enzyme production. Nevertheless, the enzyme is effectively inhibited in the liver and elsewhere.⁶ Cholesterol was measured in plasma by an automated method. Systolic blood pressure was measured at weeks 5, 6, and 7 by the tail-cuff method under light ether anesthesia. Rats were killed at 7 weeks of age. The hearts were washed with ice-cold saline, blotted dry, and weighed. For Western blot and nuclear factor-B (NF-B) analysis, the tissues were snap-frozen in liquid nitrogen for immunohistochemistry in isopentane (-35°C) and stored at -80°C.

Immunohistochemistry
Immunohistochemistry (APAAP technique) was performed as described previously.^3,4 Antibodies were purchased against monocytes/macrophages (ED1, Serotec), lymphocytes (CD4 and CD8, PharMingen), NF-B subunit p65 (Roche Boehringer), interleukin (IL)-6 (R&D Systems), c-fos, and basic fibroblast growth factor (bFGF, Santa Cruz Biotechnology, Inc). For immunofluorescence, ice-cold acetone-fixed cryosections (6 µm) were air-dried and immersed in TBS (0.05 mol/L Tris buffer, 0.15 mol/L NaCl, pH 7.6). All incubations were performed in a humid chamber at room temperature. At first, the sections were incubated in 10% normal donkey serum (Diavova) for 30 minutes to block any nonspecific binding. The sections were incubated for 60 minutes with the primary antibodies. After being washed with TBS, the sections were incubated with Cy3-conjugated secondary antibodies (donkey anti-mouse IgG-Cy3, donkey anti-rabbit IgG-Cy3, or donkey anti-goat IgG-Cy3, Dianova) for 60 minutes. After a final washing with TBS, slides were mounted in Vectashield mounting medium (Vector Laboratories). In controls, in which a primary antibody was substituted for by isotype control antibody CBL 600 mouse IgG1-negative control (Cymbus Biotechnology) at the same final concentration, no specific immunolabeling was observed. The nonspecific binding of secondary antibodies was excluded by omission of the primary antibody. Preparations were examined under a Zeiss Axioplan-2 microscope and photographed with a color reversal film Agfa CTX 100. Semiquantitative scoring of ED1-, CD4-, and CD8-positive cells in the heart was performed with a computerized cell count program (KS 300 3.0, Zeiss). Fifteen different areas of each heart sample (n=5 in all groups) were analyzed. The hearts were examined without knowledge of the rats’ identity. Collagen, fibronectin, laminin, c-fos, and p65 were assessed semiquantitatively by 2 different observers without knowledge of the rats’ identity. The data are expressed in arbitrary units (0 to 5) based on the staining intensity.

Electrophoretic Mobility Shift Assay and TaqMan Analyses
Tissue extracts and electrophoretic mobility shift assay (EMSA) for NF-B and AP-1 were performed thrice. Densitometry quantification values (NIH Image Program, version 1.61) are given in percent of untreated dTGR. Nuclear extracts of the left ventricle (10 µg) were incubated in binding reaction medium with 0.5 ng of ³²P-dATP end-labeled oligonucleotide containing the NF-B binding site from the major histocompatibility complex enhancer (H2K, 5'-GATCCAGGGCTGGGGATTCCCCATCTCCACAGG). For AP-1, double-stranded oligonucleotides containing the consensus sequence for AP-1 (Santa Cruz Biotechnology, 5'-GAT CGA ACT GAC CGC CCG CCG CCC GT-3') were radiolabeled with -³²P with the use of T4 polynucleotide kinase by standard methods and purified over a column. The DNA-protein complexes were analyzed on a 5% polyacrylamide gel 0.5% Tris buffer, dried, and autoradiographed. In competition assays, 50 ng of unlabeled H2K or AP-1 oligonucleotides was used.⁴

Primers were synthesized by Biotez (Berlin-Buch) with sequences described previously.⁴ Real-time quantitative reverse transcription–polymerase chain reaction (RT-PCR) was performed with the TaqMan system (Prism 7700 Sequence Detection System, PE Biosystems). For quantification of gene expression, the target sequence was normalized in relation to the expressed housekeeping gene GAPDH.

Statistical Analysis
Data are presented as mean±SEM. Statistically significant differences in mean values were tested by ANOVA, except for differences in blood pressure, which were tested by repeated-measures ANOVA and the Scheffé test. A value of P<0.05 was considered statistically significant. Data were analyzed with StatView statistical software.

	Results

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Nine of 20 dTGR died before the end of week 7; the mortality rate was 45%. In contrast, mortality in the cerivastatin group was 20%, and no SD rats died (P<0.001; Figure 1A). Cerivastatin treatment reduced the heart weight (P<0.05; Figure 1B). In contrast, body weight of the 3 groups was not different. Heart weights corrected for body weight were 5.9±0.23 versus 5.0±0.11 versus 3.6±0.05 mg/g for dTGR, dTGR treated with cerivastatin, and SD rats, respectively. Plasma cholesterol levels in untreated dTGR were 2.84±0.21 mmol/L compared with 2.52±0.32 mmol/L in cerivastatin-treated dTGR (Figure 1C). However, nontransgenic rats tended to lower levels (2.34±0.12 mmol/L). Differences between the 3 groups were not statistically significant (P=0.7). Systolic blood pressure of cerivastatin-treated rats was significantly decreased (54 mm Hg) compared with untreated dTGR (147±14 versus 201±06 mm Hg, P<0.001) at week 7. The dTGR showed a progressive increase in systolic blood pressure from 5 to 7 weeks. However, the blood pressure of cerivastatin-treated rats was significantly elevated compared with SD rats (147±14 versus 109±02 mm Hg, P<0.001). dTGR small vessels showed increased intimal and medial thickness. dTGR myocardial sections showed hemorrhage, patchy areas of necrosis, and interstitial fibrosis, whereas cerivastatin ameliorated the cardiac damage (data not shown).

View larger version (17K): [in this window] [in a new window]   Figure 1. A, Kaplan-Meier survival analysis in dTGR, dTGR receiving cerivastatin (CERI), and SD rats. By week 7, half of untreated dTGR were dead. In contrast, cerivastatin reduced mortality. No controls died before end of study. B, Cerivastatin also significantly reduced cardiac hypertrophy, expressed as ratio of heart weight to body weight, compared with untreated dTGR. However, cardiac hypertrophy of cerivastatin-treated dTGR was higher than in SD rats. C, Plasma cholesterol levels did not differ significantly between groups. Cerivastatin treatment did not lower plasma cholesterol levels (P=0.7).

Cerivastatin treatment reduced extracellular matrix. The hearts were stained for collagen I (Figure 2), fibronectin, and laminin (data not shown). Collagen I and fibronectin were most prominently deposited around blood vessels, in the vascular adventitia, and focally around fibrotic scarred areas. Fibronectin was also deposited in the neointima of remodeled vessels. Laminin was localized primarily between cardiomyocytes (data not shown). All 3 interstitial deposits were substantially reduced in the cerivastatin group.

View larger version (86K): [in this window] [in a new window]   Figure 2. Immunohistochemistry of cardiac tissue for collagen I from dTGR, cerivastatin-treated dTGR (CERI), and SD rats. Collagen I was increased in dTGR but was markedly decreased with cerivastatin treatment (inset shows quantification).

EMSA from 3 animals in each group showed increased NF-B (Figure 3A) and AP-1 (Figure 4A) activation in dTGR, which was reduced by cerivastatin to SD levels. Competition with unlabeled oligonucleotide and supershift experiments revealed specificity of the increased DNA binding activity for NF-B and AP-1 (Figures 3B, 3C, 4B, and 4C, respectively). A single-base-pair mutant oligonucleotide for NF-B and AP-1 showed no binding differences, indicating the specificity of the assay (Figures 3D and 4D, respectively). Quantification of NF-B and AP-1 binding activity and mutants showed that cerivastatin reduced binding by 65% and 75%, respectively (Figures 3E and 4E). mRNA expression of c-fos (Figure 4F), an important member of the AP-1 complex that was increased in dTGR, was reduced by cerivastatin. Reduced DNA binding activity for AP-1 and NF-B in response to cerivastatin treatment was confirmed by immunohistochemical expression of activated p65 (Figure 3F), the member of the NF-B family with the strongest transactivation potential, and c-fos (Figure 4G). Both transcription factors showed weak staining in SD animals; however, in dTGR, intense red staining of the vessel and perivascular region was visible. Cerivastatin reduced p65 expression and c-fos toward SD levels.

View larger version (44K): [in this window] [in a new window]   Figure 3. A, EMSA showing NF-B DNA binding activity. DNA binding was induced in dTGR and reduced with cerivastatin (CERI). Specific bands and nonspecific bands (us) are indicated. B, With unlabeled NF-B oligonucleotides, specific bands disappeared (competition). Specific antibodies to p50 and p65 resulted in supershifts. C, Addition of control antibodies to c-rel showed no supershift. Also shown are results of mutated NF-B (mut) oligonucleotides that gave similar NF-B activity for all 3 groups (D) and quantification of DNA binding activity (E). Immunohistochemistry shows expression of activated p65 (F). Nuclear red staining of activated p65 NF-B subunit in dTGR was reduced by cerivastatin.

View larger version (39K): [in this window] [in a new window]   Figure 4. A, EMSA showing AP-1 DNA binding activity. DNA binding was increased in dTGR and reduced with cerivastatin (CERI). Specific bands and nonspecific bands (us) are indicated. B, Competition with unlabeled AP-1 oligonucleotides resulted in disappearance of specific bands. C, Specific antibodies to c-fos resulted in supershift, but addition of control antibodies to Stat-1 did not. Also shown are results of single-base-pair mutation (mut) in AP-1 oligonucleotides, which resulted in similar binding activity for all 3 groups (D). E, Quantification of AP-1 and mutated AP-1 DNA binding activity. F, c-fos mRNA expression substantiated AP-1 results. Immunohistochemistry shows increased expression of c-fos in dTGR that was markedly reduced by cerivastatin (G). c-fos staining was prominent in vessel wall, perivascular area, and between myofibrils.

Untreated dTGR showed markedly increased expression of IL-6 (Figure 5A) and bFGF (Figure 5B) in the media of cardiac vessels, which was reduced by cerivastatin treatment. bFGF and IL-6 were also present in the perivascular space and between myofibrils. With cerivastatin treatment, staining for both substances was reduced (data not shown). Immunofluorescence data were confirmed by semiquantitative RT-PCR TaqMan RNA analyses for IL-6 and bFGF. bFGF and IL-6 were markedly increased in the hearts of dTGR. Cerivastatin reduced both factors close to control SD levels.

View larger version (25K): [in this window] [in a new window]   Figure 5. Immunofluorescent expression of IL-6 (A) and bFGF (B) is shown in media from cardiac vessel, as well as RNA analysis. Both factors were upregulated in dTGR and reduced by cerivastatin (CERI) on mRNA and protein levels toward control values.

We then investigated the effect of cerivastatin on cell infiltration. Staining for the macrophage marker ED1 in dTGR hearts was substantially increased around the small vessel and between cardiac muscle fibers (Figure 6A). Staining was performed in at least 5 hearts from each group, and a semiquantitative assessment for ED1 and the lymphocyte markers CD4 and CD8 was done for statistical analysis (Figure 6B). Semiquantitative analysis showed that ceriv-astatin reduced ED1-, CD4-, and CD8-positive cells significantly compared with untreated controls, although not to levels observed in SD rats. Cerivastatin had a more pronounced effect on reduction of ED1-positive and CD8-positive cells. The effect on CD4-positive cells was weaker; however, the reduction was significant for all 3 parameters (P<0.05).

View larger version (109K): [in this window] [in a new window]   Figure 6. A, Immunohistochemistry for macrophages. B, Semiquantification revealed that cerivastatin (CERI) reduced ED1-, CD4-, and CD8-positive cells in heart. Fifteen different areas of each heart were analyzed. Results are mean±SEM of 5 animals per group.

	Discussion

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We relied on a dTGR model of high Ang II–induced hypertension and end-organ damage to show that cerivastatin treatment reduces mortality, blood pressure, left ventricular hypertrophy, fibrosis (collagen I, fibronectin, and laminin deposition), and macrophage infiltration. Furthermore, bFGF expression was markedly reduced by cerivastatin, as was expression of IL-6. These results were accompanied by a marked reduction in NF-B and AP-1 activation compared with dTGR controls. We do not believe that our results were related primarily to a cerivastatin-induced reduction of blood pressure, although we cannot rule out blood pressure–related effects. Statins regularly lower blood pressure in rodent hypertension models and have been shown to be effective in a randomized, double-blind crossover trial in humans.⁷

In a previous study,³ we compared blood pressure reduction with a human renin inhibitor to hydralazine, reserpine, and hydrochlorothiazide and found that triple therapy–treated dTGR nevertheless developed severe heart and kidney damage in the face of blood pressure reduction. Although cerivastatin treatment reduced inflammation, cytokine expression, AP-1 and NF-B activity, and blood pressure, the reduction in cardiac hypertrophy was significant but incomplete. In a previous aortic banding study,⁸ a statin reduced cardiac hypertrophy in a manner similar to the effects reported here; however, an ACE inhibitor was more effective. Similar results were observed in an in vitro study of cardiomyocytes.⁹ The cerivastatin-related effects, as in the present study, were independent of cholesterol reduction. We have also made similar observations in this same model in terms of nephroprotection from Ang II–related injury.¹⁰ In that study, we found that cerivastatin inhibited extracellular-regulated kinase activation in the kidney.

We observed increased collagen I, fibronectin, and laminin deposition in dTGR hearts that was ameliorated by statin treatment. Collagen I is regulated by Ras and AP-1.¹¹ Ang II has been shown to activate the collagen I gene in transgenic mice, an effect that was blocked by losartan, raising the possibility that Ang II might directly initiate the process of organ fibrosis.¹² Previous work has demonstrated that Ang II stimulates collagen protein synthesis in cardiac myofibroblasts in vitro and increases collagen I mRNA expression in rat hearts in vivo.¹³

Cardiac hypertrophy and heart failure both feature hypertrophy of cardiomyocytes, hyperplasia of nonmyocyte cells, extracellular matrix deposition, fibrosis, vessel remodeling, cytokine activation, and inflammation. bFGF has been implicated in the pathogenesis of hypertrophy. Schultz et al¹⁴ studied a mouse with a disrupted bFGF gene. These mice developed less hypertrophy after aortic banding than wild-type mice. Paced cardiomyocytes exposed to antibodies directed at bFGF showed less hypertrophy than control cells in an in vitro study.¹⁵ bFGF was found to mediate VSMC hypertrophy, leading to vessel wall remodeling in response to Ang II treatment.¹⁶ IL-6 is important in heart failure and arteriosclerosis. In the present study, bFGF and IL-6 expression were both markedly increased in the hearts of dTGR but were reduced by cerivastatin. Interestingly, the genes for both contain NF-B and AP-1 transcription factor regulatory elements. bFGF may have been responsible in part for the increased IL-6 production. Kozawa et al¹⁷ demonstrated that bFGF induces IL-6 synthesis in osteoblasts and that this process is autoregulated by protein kinase C. On the other hand, IL-6 can also upregulate bFGF. The reciprocal interaction between these components is regulated by AP-1.¹⁸ dTGR featured both inflammation and fibrosis in the heart. The presence of inflammatory cells in hypertrophied hearts is well recognized. Nicoletti and Michel¹⁹ showed that bFGF is released by inflammatory cells, thereby mediating hypertrophy and fibrosis.

The mechanisms of the statin-related protection are unknown but may involve G proteins involved in receptor-coupled signal transduction, particularly Rho.¹⁹ The Rho proteins belong to the Ras superfamily. The Ras proteins alternate between an inactivated GDP-bound form and an activated GTP-bound form, allowing them to act as molecular switches for growth and differentiation signals. Prenylation is a process involving the binding of hydrophobic isoprenoid groups consisting of farnesyl or geranylgeranyl residues to the carboxy-terminal region of the Ras protein superfamily. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate are metabolic products of mevalonate that are able to supply prenyl groups. The prenylation is conducted by prenyl transferases. The hydrophobic prenyl groups are necessary to anchor the Ras superfamily proteins to intracellular membranes so that they can be translocated to the plasma membrane.²⁰ The final cell membrane fixation is necessary for Ras proteins to participate in their specific interactions. Several groups have presented evidence supporting such a statin-induced mechanism. For instance, Bourcier and Libby²¹ recently showed that a statin reduced plasminogen activator inhibitor-1 expression by VSMC and endothelial cells. Their study also implicated geranylgeranyl-modified intermediates and exonerated farnesyl pyrophosphate. Furthermore, Laufs and Liao²² demonstrated that Rho negatively regulates endothelial nitric oxide synthase expression and that statins upregulate endothelial nitric oxide synthase expression by blocking Rho geranylgeranylation, which is necessary for its membrane-associated activity.

Statins decrease the production of mevalonate, geranyl pyrophosphate, farnesyl pyrophosphate, and subsequent products on the way to construction of the cholesterol molecule. Thus, statins could act independently of circulating LDL by intracellularly interfering with Ras superfamily protein function. Ikeda et al²³ recently showed that statins decrease matrix metalloproteinase-1 expression through inhibition of Rho. In cultured VSMCs, HMG-CoA reductase inhibition diminished collagen I, thrombospondin, and fibronectin synthesis.²⁴ Similarly, HMG-CoA reductase inhibitors interfered with surface adhesion molecule expression by macrophages, leading to monocyte-endothelium adhesion inhibition.²⁵ Conceivably, the effects could also be related to a cholesterol-independent decreased AT1 receptor expression in response to statin treatment.²

Kureishi et al²⁶ recently showed that statins are capable of activating the Akt kinase and promote angiogenesis in normocholesterolemic rats. They found that simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase, inhibited apoptosis, and accelerated blood vessel formation. Their observations suggest that Akt may represent a mechanism by which non–cholesterol-related effects of statins may occur. Akt also activates NF-B, in addition to a host of other transcription factors, to brake apoptosis.²⁷ We would speculate that in our Ang II–related model, Akt would be activated by Ang II to participate in NF-B activation. However, that hypothesis remains to be tested. We conclude that the statins exhibit actions independent of cholesterol lowering that appear to exert vasculoprotective and anti-inflammatory effects. Finally, cerivastatin is a vascular cell–permeable statin; however, whether that feature provides any clinical advantage remains to be seen. A vascular cell–impermeable statin was found to preserve interstitial plaque collagen content in a recent animal study, whereas a vascular cell–permeable statin reduced the number of VSMCs within plaques.²⁸ Clearly, additional investigations are necessary to establish any clinical relevance of our findings.

	Acknowledgments

 
This study was supported by grants-in-aid from Hoffmann LaRoche, Basel, Switzerland; Bayer AG, Leverkusen, Germany; Klinisch-Pharmakologischer Verbund, Berlin-Brandenburg; and the Bundesministerium für Bildung und Forschung, Bonn, Germany.

	Footnotes

 
The first 3 authors contributed equally to this work.

Received December 1, 2000; revision received March 30, 2001; accepted April 5, 2001.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Khwaja A, Connolly JO, Hendry BM. Prenylation inhibitors in renal disease. Lancet. 2000; 355: 741–744.[Medline] [Order article via Infotrieve]
   
2. Nickenig G, Bäumer AT, Temur Y, et al. Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation. 1999; 100: 2131–2134.[Abstract/Free Full Text]
   
3. Mervaala E, Müller DN, Schmidt F, et al. Blood pressure-independent effects in rats with human renin and angiotensinogen genes. Hypertension. 2000; 35: 587–594.[Abstract/Free Full Text]
   
4. Müller DN, Dechend R, Mervaala EMA, et al. NF-B inhibition ameliorates Ang II-induced inflammatory damage in rats. Hypertension. 2000; 35: 193–201.[Abstract/Free Full Text]
   
5. Bischoff H, Angerbauer R, Boberg M, et al. Preclinical review of cerivastatin sodium: a step forward in HMG-CoA reductase inhibition. Atherosclerosis. 1998; 139 (suppl 1): S7–S13.
   
6. Fears R, Richards DH, Ferres H. The effect of compactin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, on cholesterogenesis and serum cholesterol levels in rats and chicks. Atherosclerosis. 1980; 35: 439–449.[Medline] [Order article via Infotrieve]
   
7. Glorioso N, Troffa C, Filigheddu F, et al. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension. 1999; 34: 1281–1286.[Abstract/Free Full Text]
   
8. Luo JD, Zhang WW, Zhang GP, et al. Simvastatin inhibits cardiac hypertrophy and angiotensin-converting enzyme activity in rats with aortic stenosis. Clin Exp Pharmacol Physiol. 1999; 26: 903–908.[Medline] [Order article via Infotrieve]
   
9. Oi S, Haneda T, Osaki J, et al. Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol. 1999; 376: 139–148.[Medline] [Order article via Infotrieve]
   
10. Park J-K, Müller DN, Mervaala EMA, et al. Cerivastatin prevents leukocyte infiltration and iNOS induction by inhibition of ERK phosphorylation and NF-B activation in angiotensin II-induced end-organ damage. Kidney Int. 2000; 58: 1420–1430.[Medline] [Order article via Infotrieve]
    
11. Slack JL, Parker MI, Roginson VR, et al. Regulation of collagen I gene expression by ras. Mol Cell Biol. 1992; 10: 4714–4723.
    
12. Boffa J-J, Tharaux P-L, Placier S, et al. Angiotensin II activates collagen type I gene in the renal vasculature of transgenic mice during inhibition of nitric oxide synthesis. Circulation. 1999; 100: 1901–1908.[Abstract/Free Full Text]
    
13. Brilla CG, Zhou G, Matsubara L, et al. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol. 1994; 26: 809–820.[Medline] [Order article via Infotrieve]
    
14. Schultz JJ, Witt SA, Nieman ML, et al. bFGF mediates pressure-induced hypertrophic response. J Clin Invest. 1999; 104: 709–719.[Medline] [Order article via Infotrieve]
    
15. Kaye D, Pimental D, Prasad S, et al. Role of transiently altered sarcolemmal membrane permeability and basic fibroblast growth factor release in the hypertrophic response of adult rat ventricular myocytes to increased mechanical activity in vitro. J Clin Invest. 1996; 97: 281–291.[Medline] [Order article via Infotrieve]
    
16. Su E, Lombardi D, Wiener J, et al. Mitogenic effect of angiotensin II on rat carotid arteries and type II or III mesenteric microvessels but not type I mesenteric microvessels is mediated by endogenous bFGF. Circ Res. 1998; 82: 321–327.[Abstract/Free Full Text]
    
17. Kozawa O, Suzuki A, Uematsu T. Basic FGF induces interleukin-6 synthesis in osteoblasts: autoregulation by protein kinase C. Cell Signal. 1997; 9: 463–468.[Medline] [Order article via Infotrieve]
    
18. Faris M, Ensoli B, Kokot N, et al. Inflammatory cytokines induce the expression of basic fibroblast growth factor (b-FGF) isoforms required for the growth of Kaposi’s sarcoma and endothelial cells through the activation of AP-1 response elements in the bFGF promoter. AIDS. 1998; 12: 19–27.[Medline] [Order article via Infotrieve]
    
19. Nicoletti A, Michel JB. Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors. Cardiovasc Res. 1999; 41: 532–543.[Abstract/Free Full Text]
    
20. Magee T, Marshall C. New insights into the interaction of Ras with the plasma membrane. Cell. 1999; 98: 9–12.[Medline] [Order article via Infotrieve]
    
21. Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol. 2000; 20: 556–562.[Abstract/Free Full Text]
    
22. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998; 273: 24266–24271.[Abstract/Free Full Text]
    
23. Ikeda U, Shimpo M, Ohki R, et al. Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. Hypertension. 2000; 36: 325–329.[Abstract/Free Full Text]
    
24. Riessen R, Axel DI, Fenchel M, et al. Effect of HMG-CoA reductase inhibitors on extracellular matrix expression in human vascular smooth muscle cells. Basic Res Cardiol. 1999; 94: 322–332.[Medline] [Order article via Infotrieve]
    
25. Weber C, Erl W, Weber KS, et al. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997; 30: 1212–1217.[Abstract]
    
26. Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000; 9: 1004–1010.
    
27. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999; 13: 2905–2927.[Free Full Text]
    
28. Fukumoto Y, Libby P, Rabkin E, et al. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits. Circulation. 2001; 103: 993–999.[Abstract/Free Full Text]
    

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				J. Habibi, A. Whaley-Connell, M. A. Qazi, M. R. Hayden, S. A. Cooper, A. Tramontano, J. Thyfault, C. Stump, C. Ferrario, R. Muniyappa, et al. Rosuvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Decreases Cardiac Oxidative Stress and Remodeling in Ren2 Transgenic Rats Endocrinology, May 1, 2007; 148(5): 2181 - 2188. [Abstract] [Full Text] [PDF]

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				L. Hauck, C. Harms, D. Grothe, J. An, K. Gertz, G. Kronenberg, R. Dietz, M. Endres, and R. von Harsdorf Critical Role for FoxO3a-Dependent Regulation of p21CIP1/WAF1 in Response to Statin Signaling in Cardiac Myocytes Circ. Res., January 5, 2007; 100(1): 50 - 60. [Abstract] [Full Text] [PDF]

				P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]

				F. Custodis, M. Eberl, H. Kilter, M. Bohm, and U. Laufs Association of RhoGDI{alpha} with Rac1 GTPase mediates free radical production during myocardial hypertrophy Cardiovasc Res, July 15, 2006; 71(2): 342 - 351. [Abstract] [Full Text] [PDF]

				S. Shibata, M. Nagase, and T. Fujita Fluvastatin Ameliorates Podocyte Injury in Proteinuric Rats via Modulation of Excessive Rho Signaling J. Am. Soc. Nephrol., March 1, 2006; 17(3): 754 - 764. [Abstract] [Full Text] [PDF]

				K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, M. H. Kang, T. H. Ahn, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients Circulation, December 14, 2004; 110(24): 3687 - 3692. [Abstract] [Full Text] [PDF]

				Y. Chen, A.-P. Arrigo, and R. W. Currie Heat shock treatment suppresses angiotensin II-induced activation of NF-{kappa}B pathway and heart inflammation: a role for IKK depletion by heat shock? Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1104 - H1114. [Abstract] [Full Text] [PDF]

				M. Ito, T. Adachi, D. R. Pimentel, Y. Ido, and W. S. Colucci Statins Inhibit {beta}-Adrenergic Receptor-Stimulated Apoptosis in Adult Rat Ventricular Myocytes via a Rac1-Dependent Mechanism Circulation, July 27, 2004; 110(4): 412 - 418. [Abstract] [Full Text] [PDF]

				N. Frey, H. A. Katus, E. N. Olson, and J. A. Hill Hypertrophy of the Heart: A New Therapeutic Target? Circulation, April 6, 2004; 109(13): 1580 - 1589. [Abstract] [Full Text] [PDF]

				K. T. Weber From Inflammation to Fibrosis: A Stiff Stretch of Highway Hypertension, April 1, 2004; 43(4): 716 - 719. [Full Text] [PDF]

				T. B. Horwich, W. R. MacLellan, and G. C. Fonarow Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure J. Am. Coll. Cardiol., February 18, 2004; 43(4): 642 - 648. [Abstract] [Full Text] [PDF]

				C. Maack, T. Kartes, H. Kilter, H.-J. Schafers, G. Nickenig, M. Bohm, and U. Laufs Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment Circulation, September 30, 2003; 108(13): 1567 - 1574. [Abstract] [Full Text] [PDF]

				D. Susic, J. Varagic, J. Ahn, M. Slama, and E. D. Frohlich Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1091 - 1097. [Abstract] [Full Text] [PDF]

				B. M. Singh and J. L. Mehta Interactions Between the Renin-Angiotensin System and Dyslipidemia: Relevance in the Therapy of Hypertension and Coronary Heart Disease Arch Intern Med, June 9, 2003; 163(11): 1296 - 1304. [Abstract] [Full Text] [PDF]

				H. L. Lazar, Y. Bao, Y. Zhang, and S. A. Bernard Pretreatment with statins enhances myocardial protection during coronary revascularization J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 1037 - 1042. [Abstract] [Full Text] [PDF]

				P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]

				D. N. Muller, A. Mullally, R. Dechend, J.-K. Park, A. Fiebeler, B. Pilz, B.-M. Loffler, D. Blum-Kaelin, S. Masur, H. Dehmlow, et al. Endothelin-Converting Enzyme Inhibition Ameliorates Angiotensin II-Induced Cardiac Damage Hypertension, December 1, 2002; 40(6): 840 - 846. [Abstract] [Full Text] [PDF]

				H. Krum and J. J. McMurray Statins and chronic heart failure: do we need a large-scale outcome trial? J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1567 - 1573. [Abstract] [Full Text] [PDF]

				N. Frey and E. N. Olson Modulating Cardiac Hypertrophy by Manipulating Myocardial Lipid Metabolism? Circulation, March 12, 2002; 105(10): 1152 - 1154. [Full Text] [PDF]

				R. Dechend, D. Muller, J. K. Park, A. Fiebeler, H. Haller, and F. C. Luft Statins and angiotensin II-induced vascular injury Nephrol. Dial. Transplant., March 1, 2002; 17(3): 349 - 353. [Full Text] [PDF]

				U. Laufs, H. Kilter, C. Konkol, S. Wassmann, M. Bohm, and G. Nickenig Impact of HMG CoA reductase inhibition on small GTPases in the heart Cardiovasc Res, March 1, 2002; 53(4): 911 - 920. [Abstract] [Full Text] [PDF]

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