Published online before print October 25, 2007, doi: 10.1161/CIRCRESAHA.107.163493
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2008 American Heart Association, Inc.
Molecular Medicine |
Pitavastatin, an HMG-CoA Reductase Inhibitor, Exerts eNOS-Independent Protective Actions Against Angiotensin II–Induced Cardiovascular Remodeling and Renal Insufficiency
From the Department of Medicine and Bioregulatory Sciences (S.Y., K.A., Y.I., Y.S., S.Y., T.I., T.I., K.I., H.A., M.A., T.M.), The University of Tokushima Graduate School of Health Biosciences, Japan; and the 21st Century Center of Excellence Program of the University of Tokushima (Y.I., T.M.), Japan.
Correspondence to Ken-ichi Aihara, MD, PhD, Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail aihara{at}clin.med.tokushima-u.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II–induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II–induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II–induced oxidative stress, cardiac TGFβ-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II–induced cardiac remodeling and diastolic dysfunction in eNOS–/– mice as in wild-type mice. In eNOS–/– mice, the Ang II–induced cardiac oxidative stress and TGF-β–Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II–treated eNOS–/– mice, with suppression of glomerular oxidative stress and TGF-β-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II–induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-β-Smad 2/3 signaling pathway by suppression of oxidative stress.
Key Words: angiotensin II • pitavastatin • eNOS • cardiorenal insufficiency
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Accumulating evidence indicates that vascular wall inflammation plays a key role in the pathogenesis of vascular diseases and atherosclerotic processes, and angiotensin II (Ang II), a key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of vascular tone, blood pressure (BP), and electrolyte homeostasis.1 Ang II induces inflammation through BP-dependent and -independent mechanisms, and Ang II accelerates cardiovascular remodeling through enhanced oxidative stress,1 vascular permeability,2 leukocyte infiltration,3–5 and tissue remodeling.6 Because numerous clinical studies have shown that an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) prevent cardiovascular events and remodeling,7–10 blockade of the RAS system is one of the major strategies for treatment of cardiovascular diseases.
In addition to ACE inhibitors and ARBs, it has been shown that statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are effective in preventing cardiovascular events11–14 and ameliorating endothelial dysfunction.15 These effects of statins cannot be explained merely by their lipid-lowering effects.16–18 In fact, statins have been reported to have pleiotropic actions, including activation and upregulation of the eNOS system,15 reduction of oxidative stress and inflammatory cytokines,19–21 and regulation of thrombogenesis-related gene expression.22,23 However, the mechanisms by which statins exert these actions remain elusive. Because the transforming growth factor (TGF)-β–Smad signaling pathway participates in the pathogenesis of multiple cardiovascular and renal diseases,24,25 we speculated that there is an interplay between Ang II–induced organ damage and pleiotropic effects of statins and that these factors are linked with regulation of the TGF-β–Smad signaling pathway.
To elucidate the cardiovascular protective effects as well as the mechanism of action of statins against the activated RAS, we performed studies using Ang II–infused mice with or without pitavastatin administration. The present study provides novel in vivo evidence that pitavastatin exerts eNOS-independent protective effects against Ang II–induced cardiovascular remodeling and renal insufficiency with suppression of oxidative stress and inhibition of the TGF-β1-Smad 2/3 signaling pathway.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals and Experimental Protocol
We used 10-week-old C57BL6/J male mice and they were sham-operated or subcutaneously infused with Ang II (WAKO Tokyo, Japan) at a rate of 2.0 mg/kg/d for 2 weeks by an osmotic mini-pump (Alzet model 1002, Alza Corp, Mountain View, Calif).26 They were divided into 2 groups, ad libitum administration of pitavastatin (NK 104 Kowa Pharmaceutaical Co. Ltd) or a vehicle. In the same way, we examined eNOS–/– male mice (The Jackson Laboratory, Bar Harbor, Me) with or without Ang II stimulation, and they were simultaneously administered oral pitavastatin at 0.3 mg/kg/d or a vehicle. Pitavastatin, a lipophilic HMG CoA reductase inhibitor, is categorized as a strong statin. Pitavastatin was chosen for this study because it is hardly metabolized by the cytochrome P450 system. Such characteristics give pitavastatin considerable advantages over other statins that are metabolized by cytochrome P450. These advantages include extremely weak expected interactions with many other commonly used drugs as well as its high serum concentrations after absorption from the small intestine, enabling its direct actions on cardiovascular and renal systems.27 Pitavastatin was dissolved in drinking water at a concentration of 2.5 mg/L. Average daily amounts of drinking water for wild-type C57BL6/J mice and eNOS–/– mice were about 3.0 mL and 2.5 mL, respectively, and average body weights were about 26 to 27 g and 22 to 24 g, respectively (Table). Therefore, estimated intake of pitavastatin was approximately 0.3 mg/kg/d. We also evaluated plasma concentrations of pitavastatin by HPLC and confirmed that plasma pitavastatin concentration in mice with pitavastatin treatment was comparable to and below that observed in clinical use (supplemental data I, available online at http://circres.ahajournals.org). The survival experiment in eNOS–/– mice was performed with 25 mice in each group. Twenty-five mice with pitavastatin treatment and the same number of mice without pitavastatin treatment were infused with Ang II by 14-day release osmotic mini-pumps. The survival rates of those mice were estimated for 14 days during Ang II infusion, and mice that survived were euthanized for analyses. All experimental procedures were performed in accordance with the guidelines of the Animal Research Committee, The University of Tokushima Graduate School.
|
We performed the following experimental procedures: measurements of blood pressure and heart rate, measurements of plasma lipid and glucose levels, echocardiographic analysis, histological analysis and immunohistochemistry, analysis of urinary excretion of 8-hydroxy-2'-deoxyguanosine(8-OHdG), Western blot analysis, superoxide detection in myocardial and renal tissues, evaluation of urinary albumin excretion and glomerular filtration rate, and statistical analysis as detailed in the online data supplement (supplemental data II).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Blood Pressure and Heart Rate
Systolic, diastolic, and mean BP levels were elevated by Ang II infusion. Pitavastatin treatment did not affect BP levels regardless of Ang II infusion. There was no significant difference in heart rate among the groups (Table).
Plasma Lipid Profiles and Glucose Levels
Ang II infusion caused a significant elevation of plasma total cholesterol levels both in pitavastatin-treated and untreated mice (Table). Plasma total cholesterol levels tended to be lower in vehicle-treated mice with pitavastatin. However, pitavastatin did not have statistically significant influence on any parameters of plasma lipid and glucose levels among the groups of mice (Table).
Pitavastatin Prevents Ang II–Induced Cardiac Hypertrophy and Diastolic Dysfunction
Ultrasonographic studies to examine cardiac dimension revealed that Ang II stimulation caused significant increases in relative wall thickness (RWT) and left ventricular mass index (LVMI) in vehicle-treated mice. However, Ang II treatment did not significantly increase RWT or LVMI in pitavastatin-treated mice (Figure 1). We also evaluated cardiac performance of these mice using ultrasonography (Figure 1). Although LV fractional shortening (LVFS), a marker of systolic function, was not significantly influenced by either Ang II or pitavastatin treatment, Ang II stimulation significantly attenuated LV diastolic function as indicated by a lower E-to-A wave velocity ratio, prolonged deceleration time, and decreased deceleration rate in transmitral Doppler flow in mice. In contrast, pitavastatin treatment ameliorated the impairment in all of these parameters of LV diastolic function caused by Ang II.
|
Pitavastatin Attenuates Ang II–Induced Cardiomyocyte Hypertrophy and Remodeling of the Coronary Artery
Cross-sectional histopathological examinations of the heart revealed that Ang II evoked cardiac hypertrophy with increased cardiac fibrosis. Ang II also increased perivascular fibrosis around the coronary artery. Pitavastatin treatment attenuated those Ang II–induced cardiovascular fibrotic changes (Figure 2a). Quantitative analyses of microscopic findings of left cardiac ventricular tissues revealed that Ang II caused hypertrophic changes of cardiomyocytes with marked interstitial fibrosis, along with accelerated perivascular fibrosis and medial thickening of the coronary artery. Pitavastatin treatment prevented the development of all these adverse phenotypes of Ang II–induced cardiovascular remodeling, and no significant Ang II–induced increase in the size of cardiomyocytes, myocardial fibrosis, or intima-medial thickening was observed in pitavastatin-treated mice (Figure 2b).
|
Pitavastatin Reduces Ang II–Induced Oxidative Stress
Because statins have been shown to improve endothelial dysfunction partly through their antioxidant potency, we estimated urinary excretion of 8-OHdG as an oxidative stress marker. Ang II treatment caused a notable increase of urinary 8-OHdG excretion in vehicle-treated mice, whereas pitavastatin treatment significantly attenuated the Ang II–induced elevation of urinary 8-OHdG excretion (Figure 3d). In parallel with these observations, DHE-positive spots indicating superoxide production were markedly increased in the myocardium and coronary artery by Ang II stimulation in vehicle-treated mice (Figure 3a). In contrast, pitavastatin treatment blunted the increase in DHE-positive spots in Ang II–infused mice (Figure 3a).
|
Pitavastatin Attenuates Ang II–Induced Cardiac Expression of TGF- β1 and Smad 2/3 Activation
TGF- β1 plays an important role in cardiac hypertrophy and fibrosis, and Ang II is known to enhance TGF-β1 expression. On binding of TGF- β1 to its receptor, phosphorylation and nuclear translocation of Smad 2/3 constitute a critical step in the TGF-β1 signaling pathway. In an effort to clarify the mechanism of action of pitavastatin in the prevention of Ang II–induced cardiac remodeling, we examined the effects of pitavastatin on cardiac TGF-β1 expression and Smad 2/3 activation in Ang II–infused mice (Figure 3a, 3b, 3c). Ang II stimulation caused a marked enhancement in cardiac TGF-β1 expression and phosphorylation of Smad 2/3 in vehicle-treated mice. In contrast, pitavastatin treatment significantly attenuated these changes caused by Ang II, and no significant Ang II–induced changes in these parameters were observed in pitavastatin-treated mice (Figure 3a, 3b, 3c).
Pitavastatin Ameliorates Left Ventricular Hypertrophy and Diastolic Dysfunction in Ang II–Treated eNOS–/– Mice
Recent studies have indicated that cardiovascular effects of statins involve eNOS activation.28,29 To clarify whether cardioprotective effects of pitavastatin depend on eNOS activation, we studied the effect of pitavastatin on cardiovascular remodeling using Ang II–treated eNOS–/– mice. As shown in the Table, Ang II–treated eNOS–/– mice showed significant weight loss, whereas pitavastatin restored the change. Cardiac ultrasonography showed that both RWT and LVMI were markedly increased by Ang II stimulation in eNOS–/– mice (Figure 4). Pitavastatin treatment almost completely abrogated those changes, similar to the results in wild-type C57BL6/J mice. Although there were no significant changes in LVFS among all groups, diastolic function evaluated by trans-mitral Doppler flow was disturbed by Ang II treatment in eNOS–/– mice as observed in wild-type mice (Figure 4). Pitavastatin again ameliorated the impaired LV diastolic function by correcting the E-to-A wave ratio, deceleration time, and deceleration rate in Ang II–treated eNOS–/– mice (Figure 4).
|
Pitavastatin Attenuates Ang II–Induced Cardiomyocyte Hypertrophy and Fibrosis and Remodeling of the Coronary Artery in eNOS–/– Mice
Cross-sectional histopathological studies of the myocardium revealed that Ang II caused hypertrophic changes of cardiomyocytes with marked interstitial cardiac fibrosis in eNOS–/– mice (Figure 5a and 5b). Ang II also accelerated perivascular fibrosis and medial thickening of the coronary artery in eNOS–/– mice (Figure 5a and 5b) as well as in wild-type C57BL6/J mice (Figure 2). Pitavastatin treatment attenuated these phenotypes of Ang II–induced cardiovascular remodeling in eNOS–/– mice (Figure 5a and 5b).
|
Pitavastatin Attenuates Ang II–Induced Oxidative Stress in eNOS–/– Mice
Dihydroethidium (DHE) staining showed that Ang II increased superoxide production in cardiomyocytes and coronary arteries of eNOS–/– mice (Figure 6a). DHE staining at the myocardium and the coronary artery was decreased by pitavastatin treatment in Ang II–treated eNOS–/– mice (Figure 6a).
|
Pitavastatin Attenuates AngII–Induced TGF-β1 Expression and Smad 2/3 Phosphorylation in the Myocardium and the Coronary Artery in eNOS–/– Mice
Ang II–induced TGF- β1 expression in the myocardium and the coronary artery evaluated by Western blot and immunohistochemistry was enhanced in eNOS–/– mice (Figure 6a and 6b). Cardiac Smad 2/3 phosphorylation was also enhanced by Ang II stimulation in eNOS–/– mice (Figure 6c). The increased TGF-β1 expression and increased Smad 2/3 phosphorylation in the myocardium of Ang II–treated eNOS–/– mice were attenuated by pitavastatin treatment (Figure 6a, 6b, 6c).
Pitavastatin Improves Survival Rate and Glomerular Injury in AngII–Treated eNOS–/– Mice
Although survival rate and renal phenotypes were not altered in Ang II–treated wild-type C57BL6/J mice (The results of renal studies in wild-type C57BL6/J mice are shown as supplemental data III), Ang II stimulation markedly decreased survival rate of eNOS–/– mice with decreased daily urinary output and GFR along with increased urinary albumin excretion (Figure 7a and 7b). Immunohistochemical examinations revealed that PAS- and fibrin(ogen)- positive glomerular depositions were increased by Ang II treatment and that glomerular TGF-β1 and DHE staining was also increased in Ang II–treated eNOS–/– mice (Figure 7c). In contrast, pitavastatin treatment improved the survival rate as well as renal function and glomerular remodeling of Ang II–treated eNOS–/– mice (Figure 7a to 7c). The enhancement of renal TGF-β1 expression and Smad 2/3 phosphrylation by Ang II stimulation of eNOS–/– mice was also attenuated by pitavastatin treatment (Figure 7d).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study demonstrated that pitavastatin has protective actions against Ang II–induced cardiovascular remodeling through inhibition of the TGF-β–Smad 2/3 signaling pathway by suppression of oxidative stress. Furthermore, although statins are reported to activate the eNOS system and the cardiovascular effects of statins may involve activation of eNOS, pitavastatin also showed protective actions against cardiovascular and renal impairment in eNOS–/– mice.
In wild-type mice, our results are consistent with the results of a recent study showing that rosuvastatin administration ameliorated cardiovascular remodeling with suppression of accentuated myocardial expression of gp91phox, p40phox, p22phox, and Rac-1 in transgenic rats overexpressing the mouse renin gene.30 Previous studies have also shown that statins can prevent Ang II–induced cardiovascular remodeling through inhibition of the actions of small G proteins, including Rac-1, Rho A, and p21ras,31,32 and reduction of NAD(P)H subunit p22phox.33 In addition, pitavastatin has been reported to suppress myocardial endothelin-1 expression and reduce cardiac fibrosis in Dahl salt-sensitive rats.34 Thus, the reduction in oxidative stress caused by pitavastatin may be explained at least in part by suppression of Ang II–induced enhancement in myocardial expression of NAD(P)H subunits, leading to suppression of superoxide generation.
LV diastolic dysfunction has been recognized as an early-phase manifestation of heart failure. Impaired LV diastolic function is associated with an acceleration of cardiac interstitial fibrosis leading to increased LV wall stiffness, and progression of LV diastolic dysfunction leads to the development of LV systolic failure.35 Because pitavastatin reduced fibrotic changes surrounding cardiomyocytes and coronary arteries in Ang II–treated mice, the improvement of LV diastolic dysfunction by pitavastatin can be explained by an inhibition of fibrotic changes by pitavastatin. In the present study, pitavastain treatment suppressed Ang II–induced enhancement of cardiac TGF-β1 expression and Smad 2/3 signaling. TGF-β1 is one of the most important fibrotic factors, and Smad proteins are an essential component of the intracellular signaling pathway to induce fibrosis by TGF-β1.36 Overexpression of TGF- β1 in transgenic mice results in cardiac hypertrophy characterized by both interstitial fibrosis and hypertrophic growth of cardiac myocytes. In contrast, heterozygous TGF-β1–deficient mice exhibited decreased fibrosis of the heart with aging,37 and complete TGF-β1 knockout completely abolished Ang II–induced increase in left ventricular mass and myocyte size, deterioration in systolic function, and induction of atrial natriuretic factor.38 In addition, it has been reported that Ang II–induced hypertensive vascular fibrosis is associated with activation of the TGF-β1–Smad 2/3 signaling pathway39 and that the ACE inhibitor captopril prevents cardiac fibrosis by blocking collagen production in Ang II–hypertensive rats, with an inhibition of TGF-β-Smad 2 signaling.40 Taken together, those results indicate that the RAS enhances cardiovascular remodeling and fibrotic changes by increasing TGF-β expression and thereby enhancing TGF-β-Smad 2/3 signaling. Thus, the present observations as well as those previous results are consistent with the notion that Ang II increases TGF-β expression and Smad 2/3 signaling via enhanced superoxide generation and that pitavastatin can counteract Ang II–induced cardiovascular remodeling and fibrotic changes via the inhibition of TGF-β-Smad 2/3 signaling attributable to suppression of superoxide generation enhanced by Ang II.
Accumulating evidence indicates that reduced NO bioavailability plays an important role in the development of heart failure.41 Endothelial dysfunction and decreased NO bioavailability are associated with the development of cardiovascular diseases,42 and statins enhance NO bioavailability by promoting NO production and preventing superoxide-induced NO inactivation.43,44 In a study using eNOS–/– mice, Landmesser et al demonstrated that increased NO bioavailability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after myocardial infarction.41 It has also been reported that the effect of a low dose of simvastatin on survival after myocardial infarction was abrogated in eNOS–/– mice and that rosuvastatin did not affect myocardial infarct size in eNOS–/– mice in contrast to wild-type mice.45,46 Thus, eNOS activation is required for amelioration of survival rate and attenuation of infarct size induced by at least some statins including simvastatin and rosuvastatin.
To determine whether the cardiovascular protective action of pitavastatin against Ang II excess requires increased NO bioavailability by eNOS activation, we examined the effects of pitavastatin on cardiovascular phenotypes of Ang II–treated eNOS–/– mice. Unexpectedly, pitavastatin treatment ameliorated Ang II–induced cardiac hypertrophy, perivascular fibrosis with medial thickening of coronary artery, and LV diastolic dysfunction even in eNOS–/– mice. Pitavastatin treatment also attenuated Ang II–induced increase in superoxide production, TGF-β1 expression, and Smad 2/3 phosophorylation at the myocardium and the coronary artery in eNOS–/– mice as well as in wild-type mice. These results indicate that the protective effects of pitavastatin against Ang II–induced cardiovascular remodeling do not require increased NO bioavailability by eNOS activation. However, these observations do not rule out the possibility that bioavailability of NO from other sources may be increased by pitavastatin.
The present study demonstrated for the first time that Ang II stimulation causes high mortality with decreased GFR and increased albuminuria in eNOS–/– mice. Immunohistochemistry and DHE staining demonstrated accelerated plasma protein deposition and fibrosis with increased superoxide production at the glomerulus in Ang II–treated eNOS–/– mice. It has also been demonstrated that eNOS–/– mice manifest progressive focal renal abnormalities, including glomerular hypoplasia and tubular cell death,47 suggesting that eNOS may play an important role in the protection of renal function. In the present study, we only analyzed the surviving mice at the end of observation period on day 14, and actual Ang II–induced cardio-renal damage in eNOS–/– mice might be more severe than the results we obtained. Nevertheless, it is noteworthy that pitavastatin treatment ameliorated the decrease in GFR, the increase in albuminuria and the pathological glomerular changes, and reduced the high mortality rate of Ang II–treated eNOS–/– mice. Amelioration of Ang II–induced pathological glomerular changes by pitavastatin was associated with reduced renal oxidative stress along with suppressed TGF-β1 expression and Smad 2/3 phosphorylation in eNOS–/– mice. Because TGF-β plays a major role in the accumulation of extracellular matrix during renal fibrosis, the present results are consistent with the notion that suppression of the TGF-β–Smad 2/3 signaling pathway via inhibition of superoxide production by pitavastatin treatment leads to renal protection against RAS activation.
Because other statins such as simvastatin,19 rosvastatin,30 and atorvastatin48 also reduced Ang II–induced oxidative stress, there is a possibility that the observed cardiovascular and renal protective effects of pitavastatin are class effects of statins. However, the advantageous characteristics of pitavastatin, ie, the fact that it is hardly metabolized by hepatic cytochrome p450 after intestinal absorption and the fact that it shows high cardiovascular and renal tissue distribution, may make it as one of the most potent statins to develop pleiotropic effects including cardiovascular and renal protection. To clarify this issue, further in vivo examinations to compare the effects of various orally administered statins are needed.
In conclusion, the present study demonstrated that pitavastatin exerts eNOS-independent protective actions against Ang II–induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-β-Smad 2/3 signaling pathway by suppression of oxidative stress.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported in part by Grants-in-Aid for Scientific Research and a Grant for the 21st Century Center of Excellence Program from the Ministry of Education, Science, Sports and Culture of Japan, a Grant for a Study Group on Aseptic Femoral Neck Necrosis from the Ministry of Health, Labor, and Welfare of Japan, and grants from The Uehara Memorial Foundation, and grant for Clinical Vascular Function from the Kimura Memorial Cardiovascular Foundation.
Disclosures
None.
|
Footnotes |
|---|
*The first three authors contributed equally to this study.
Original received May 2, 2007; resubmission received September 10, 2007; revised resubmission received October 2, 2007; accepted October 17, 2007.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.
2. Victorino GP, Newton CR, Curran B. Effect of angiotensin II on microvascular permeability. J Surg Res. 2002; 104: 77–81.[CrossRef][Medline] [Order article via Infotrieve]
3. Alvarez A, Cerda-Nicolas M, Naim Abu Nabah Y, Mata M, Issekutz AC, Panes J, Lobb RR, Sanz MJ. Direct evidence of leukocyte adhesion in arterioles by angiotensin II. Blood. 2004; 104: 402–408.
4. Kim JA, Berliner JA, Nadler JL. Angiotensin II increases monocyte binding to endothelial cells. Biochem Biophys Res Commun. 1996; 226: 862–868.[CrossRef][Medline] [Order article via Infotrieve]
5. Krejcy K, Eichler HG, Jilma B, Kapiotis S, Wolzt M, Zanaschka G, Gasic S, Schutz W, Wagner O. Influence of angiotensin II on circulating adhesion molecules and blood leukocyte count in vivo. Can J Physiol Pharmacol. 1996; 74: 9–14.[CrossRef][Medline] [Order article via Infotrieve]
6. Mervaala E, Muller DN, Schmidt F, Park JK, Gross V, Bader M, Breu V, Ganten D, Haller H, Luft FC. Blood pressure-independent effects in rats with human renin and angiotensinogen genes. Hypertension. 2000; 35: 587–594.
7. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999; 354: 1751–1756.[CrossRef][Medline] [Order article via Infotrieve]
8. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000; 355: 253–259.[CrossRef][Medline] [Order article via Infotrieve]
9. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
10. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861–869.
11. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285: 1711–1718.
12. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.[CrossRef][Medline] [Order article via Infotrieve]
13. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998; 97: 1440–1445.
14. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996; 335: 1001–1009.
15. Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res. 2005; 97: 1232–1235.
16. O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997; 95: 1126–1131.
17. Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm JC, Alexander RW. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995; 332: 481–487.
18. Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, Manes C, Fischer D, de Groot K, Fliser D, Fauler G, Marz W, Drexler H. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation. 2005; 111: 2356–2363.
19. Delbosc S, Cristol JP, Descomps B, Mimran A, Jover B. Simvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension. 2002; 40: 142–147.
20. Tsubouchi H, Inoguchi T, Sonta T, Sato N, Sekiguchi N, Kobayashi K, Sumimoto H, Utsumi H, Nawata H. Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement. Free Radic Biol Med. 2005; 39: 444–452.[CrossRef][Medline] [Order article via Infotrieve]
21. Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation. 2003; 108: 839–843.
22. Markle RA, Han J, Summers BD, Yokoyama T, Hajjar KA, Hajjar DP, Gotto AM Jr, Nicholson AC. Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells. J Cell Biochem. 2003; 90: 23–32.[CrossRef][Medline] [Order article via Infotrieve]
23. Masamura K, Oida K, Kanehara H, Suzuki J, Horie S, Ishii H, Miyamori I. Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family. Arterioscler Thromb Vasc Biol. 2003; 23: 512–517.
24. Ruiz-Ortega M, Rodriguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J. TGF-beta signaling in vascular fibrosis. Cardiovasc Res. 2007; 74: 196–206.
25. Bottinger EP. TG. F-beta in renal injury and disease. Semin Nephrol. 2007; 27: 309–320.[Medline] [Order article via Infotrieve]
26. Ikeda Y, Aihara K, Sato T, Akaike M, Yoshizumi M, Suzaki Y, Izawa Y, Fujimura M, Hashizume S, Kato M, Yagi S, Tamaki T, Kawano H, Matsumoto T, Azuma H, Kato S. Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. J Biol Chem. 2005; 280: 29661–29666.
27. Kajinami K, Mabuchi H, Saito Y. NK-104: a novel synthetic HMG-CoA reductase inhibitor. Expert Opin Investig Drugs. 2000; 9: 2653–2661.[CrossRef][Medline] [Order article via Infotrieve]
28. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998; 273: 24266–24271.
29. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000; 6: 1004–1010.[CrossRef][Medline] [Order article via Infotrieve]
30. Habibi J, Whaley-Connell A, Qazi MA, Hayden MR, Cooper SA, Tramontano A, Thyfault J, Stump C, Ferrario C, Muniyappa R, Sowers JR. Rosuvastatin, a HMG-CoA Reductase Inhibitor, Decreases Cardiac Oxidative Stress and Remodeling in Ren2 Transgenic Rats. Endocrinology. 2007; 148: 2181–2188.
31. Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G. Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res. 2002; 53: 911–920.
32. Oi S, Haneda T, Osaki J, Kashiwagi Y, Nakamura Y, Kawabe J, Kikuchi K. Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol. 1999; 376: 139–148.[CrossRef][Medline] [Order article via Infotrieve]
33. Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, Itter G, Rosen R, Bohm M, Nickenig G. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension. 2001; 37: 1450–1457.
34. Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Nishizawa T, Noda A, Izawa H, Nagata K, Murohara T, Yokota M. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol. 2006; 47: 770–779.[CrossRef][Medline] [Order article via Infotrieve]
35. Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007; 117: 568–575.[CrossRef][Medline] [Order article via Infotrieve]
36. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000; 14: 627–644.
37. Brooks WW, Conrad CH. Myocardial fibrosis in transforming growth factor beta(1)heterozygous mice. J Mol Cell Cardiol. 2000; 32: 187–195.[CrossRef][Medline] [Order article via Infotrieve]
38. Schultz Jel J, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest. 2002; 109: 787–796.[CrossRef][Medline] [Order article via Infotrieve]
39. Wang W, Huang XR, Canlas E, Oka K, Truong LD, Deng C, Bhowmick NA, Ju W, Bottinger EP, Lan HY. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ Res. 2006; 98: 1032–1039.
40. Peng H, Carretero OA, Vuljaj N, Liao TD, Motivala A, Peterson EL, Rhaleb NE. Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation. 2005; 112: 2436–2445.
41. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, Spiekermann S, Hilfiker-Kleiner D, Templin C, Kotlarz D, Mueller M, Fuchs M, Hornig B, Haller H, Drexler H. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation. 2004; 110: 1933–1939.
42. Liao JK, Bettmann MA, Sandor T, Tucker JI, Coleman SM, Creager MA. Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis. Circ Res. 1991; 68: 1027–1034.
43. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97: 1129–1135.
44. Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation. 2002; 105: 933–938.
45. Yamakuchi M, Greer JJ, Cameron SJ, Matsushita K, Morrell CN, Talbot-Fox K, Baldwin WM, 3rd, Lefer DJ, Lowenstein CJ. HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. Circ Res. 2005; 96: 1185–1192.
46. Greer JJ, Kakkar AK, Elrod JW, Watson LJ, Jones SP, Lefer DJ. Low-dose simvastatin improves survival and ventricular function via eNOS in congestive heart failure. Am J Physiol Heart Circ Physiol. 2006; 291: H2743–H2751.
47. Forbes MS, Thornhill BA, Park MH, Chevalier RL. Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury. Am J Pathol. 2007; 170: 87–99.
48. Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz W, Bohm M, Nickenig G. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002; 22: 300–305.
This article has been cited by other articles:
 |
|
 |
|
  S.-A Chang, Y.-J. Kim, H.-W. Lee, D.-H. Kim, H.-K. Kim, H.-J. Chang, D.-W. Sohn, B.-H. Oh, and Y.-B. Park Effect of Rosuvastatin on Cardiac Remodeling, Function, and Progression to Heart Failure in Hypertensive Heart With Established Left Ventricular Hypertrophy Hypertension, September 1, 2009; 54(3): 591 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Briones, N. Rodriguez-Criado, R. Hernanz, A. B. Garcia-Redondo, R. R. Rodrigues-Diez, M. J. Alonso, J. Egido, M. Ruiz-Ortega, and M. Salaices Atorvastatin Prevents Angiotensin II-Induced Vascular Remodeling and Oxidative Stress Hypertension, July 1, 2009; 54(1): 142 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ikeda, K.-i. Aihara, S. Yoshida, T. Sato, S. Yagi, T. Iwase, Y. Sumitomo, T. Ise, K. Ishikawa, H. Azuma, et al. Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling Endocrinology, June 1, 2009; 150(6): 2857 - 2864. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||