Skip Navigation

European Journal of Heart Failure 2009 11(1):6-13; doi:10.1093/eurjhf/hfn002
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Yang, Y.
Right arrow Articles by Fu, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, Y.
Right arrow Articles by Fu, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Beneficial effect of rosuvastatin on cardiac dysfunction is associated with alterations in calcium-regulatory proteins

Ying Yang1,{dagger}, Yun Mou1,{dagger}, Shen-Jiang Hu1,2,* and Michael Fu3

1 Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, P.R. China
2 Division of Nitric Oxide and Inflammatory Medicine, E-Institute of Shanghai Universities, Shanghai, P.R. China
3 Heart Failure Center, Department of Medicine, Sahlgrenska University Hospital/Sahlgrenska, Gothenburg, Sweden

* Corresponding author. Tel: +86 571 85519933, Fax: +86 571 88828822. Email: s0hu0001{at}hotmail.com


   Abstract
Top
 Notes
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Aims: The normal expression of Ca2+-regulatory protein is critical for efficient myocardial function. The present study tested the hypothesis that rosuvastatin treatment may attenuate left ventricular (LV) remodelling and dysfunction in the failing heart, which may be associated with alterations of Ca2+-regulatory protein.

Methods and results: We investigated the change of LV remodelling and function in a rat model of cardiac dysfunction due to myocardial infarction (MI) with or without rosuvastatin (10 mg/kg/day) treatment for 10 weeks. The protein expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA)2a, phospholamban (PLB), and phospho-PLB at serine-16 (pSer16-PLB), as well as SERCA activity, interleukin (IL)-6, and IL-10 levels were evaluated. After rosuvastatin treatment, LV remodelling and dysfunction were prevented. Rosuvastatin prevented the decrease of SERCA2a and pSer16-PLB expression, increased SERCA activity, but showed no effect on PLB expression. Furthermore, rosuvastatin reduced the increased IL-6 level and further elevated IL-10 level in the peri-infarct and remote zones of MI. Serum lipid levels remained unchanged.

Conclusion: Rosuvastatin is effective in preventing LV remodelling and dysfunction in the failing heart. The molecular mechanism may be related to normalization of SERCA2a expression, SERCA activity, and pSer16-PLB levels, as well as through cytokine alterations independent of its lipid-lowering effect.

Key Words: Rosuvastatin • Myocardial infarction • Cardiac dysfunction • Sarcoplasmic reticulum Ca2+ ATPase • Phospholamban • Interleukin

Received November 30, 2007; Revised August 28, 2008; Accepted September 12, 2008


   Introduction
Top
 Notes
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Intracellular Ca2+ homeostasis is essential for myocardial function. Sarcoplasmic reticulum Ca2+ ATPase (SERCA), mainly represented by the SERCA2a isoform in the heart,1 determines the Ca2+ loading of the sarcoplasmic reticulum (SR) and therefore the amount of Ca2+ release and cardiac contractility.2 Deteriorating function of the failing heart has been partially attributed to dysfunction of phospholamban (PLB)-controlled SERCA pump activity.3 Non-phosphorylated PLB keeps the Ca2+ affinity of SERCA low, resulting in decreased SR Ca2+ uptake, slowed relaxation, and decreased SR Ca2+ load, whereas serine-16 phosphorylation of PLB by protein kinase A in response to β-adrenergic stimulation relieves this inhibition.4

Statin therapy for cardiac dysfunction patients is still a controversial issue. Several large-scale studies are currently underway.5,6 However, some research indicates that statins can attenuate ventricular remodelling and improve ventricular function after myocardial infarction (MI).7 More importantly, statins can influence Ca2+ stores in cardiomyocytes.8

Although rosuvastatin, a new statin, was also reported for its vascular and cardioprotective effects,9 few studies have explored the effects of rosuvastatin on calcium-regulatory proteins in cardiac dysfunction. To address the possible influence of rosuvastatin on cardiac function, we used a rat model of cardiac dysfunction due to MI. In order to explore the molecular mechanism, our specific focus was to examine the effects of rosuvastatin on alterations in SERCA2a, PLB, and phospho-phospholamban at serine-16 (pSer16-PLB) in the rat myocardium. Since statins have received special attention due to their effects on proinflammatory cytokines,10 we also investigated whether rosuvastatin can change interleukin (IL)-6 and IL-10 levels.


   Methods
Top
 Notes
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
Animal preparation
The investigation conformed to the Guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85–23, revised 1996). Adult male Sprague–Dawley rats (weight, 200–250 g) were anaesthetized with 4% chloral hydrate. The left coronary artery was ligated 2–3 mm from its origin. Approximately 70% of the rats survived the procedure. For sham-operated animals, the suture was placed but not ligated (S group, n = 8). After these procedures, all rats were housed in polypropylene cages and maintained under controlled temperature conditions on a 12 h light–dark cycle with free access to food and water. One day after ligation, the animals were randomized to receive gavage with either 1 mL day–1 distilled water (MI group, n=8) or 10 mg kg–1 day–1 rosuvastatin (AstraZeneca Pharmaceutical Co., Sweden), dissolved in 1 mL distilled water, for 10 weeks (MI+R group, n = 6). Normal control (NC group, n = 8) and normal control plus rosuvastatin treatment rats (NC+R group, n = 8) were randomly selected.

Echocardiography
Rats were evaluated 2, 4, 6, 8, and 10 weeks after operation. Short- and long-axis images were acquired with a 6–12 MHz transducer (SONOS 5500). Left ventricular (LV) internal diameter at end-diastolic phase (LVIDd) and LV internal diameter at end-systolic phase (LVIDs) were measured. LV shortening fraction (FS) was calculated according to the modified Simpson method. Infarct size was calculated using the following formula: inner infarct length/(inner LV circumference+outer LV circumference)x1/2.11 All measurements were averaged for three consecutive cardiac cycles and carried out by an experienced technician who was blinded to the group identity.

Haemodynamic measurement
Ten weeks after MI, rats were anaesthetized, and haemodynamic variables were measured via a polyethylene tube filled with heparin/saline solution inserted into the right carotid artery. After balancing with atmospheric pressure, the ascending aortic blood pressure (BP) was recorded with a biosignal system (MedLab-U/4CS, China) via a pressure transducer. The tube was then inserted into the LV to record LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), and the maximal rate of rise and fall of pressure (±dp/dtmax).

Serum lipid measurement
Serum total cholesterol, triglycerides, and low- and high-density lipoprotein cholesterol were measured in a routine diagnostic analyser (Hitachi 7600, Japan) using enzymatic colorimetric assays.

Weighing of heart and infarct-size measurement
LV relative weight (LVRW) and right ventricular relative weight (RVRW) were obtained, when the LV actual weight (LVAW) and right ventricular actual weight (RVAW) were corrected for body weight. The heart tissue was cut into 5-µm-thick cross-section at the papillary muscle level, fixed in 10% formalin, and then dehydrated and embedded in paraffin. One 5-µm section was obtained from this slice and stained with haematoxylin–eosin. The outer and inner infarct length, and the outer and inner LV circumferences were measured with ImageJ 1.36 analysis software (Macintosh). The myocardial infarct size on each paraffin section was calculated as the ratio of the outer infarct length to the outer LV circumference, and the inner infarct length to the inner LV circumference (perimeter method).

Determination of sarcoplasmic reticulum Ca2+ ATPase activity
SR was prepared from LV tissue according to the method described by Jones and modified by Kodavanti et al.12,13 Protein content of the SR was measured by the Bradford method. SERCA activity was detected by measuring the Pi liberated from ATP hydrolysis according to the instructions provided with the kit (Jiancheng Co., China). One micromole of inorganic phosphorus produced by ATP decomposition of 1 mg of protein per hour was defined as the ATP activity unit.

Western blotting
Protein samples were electrophoresed on 10% sodium dodecylsulfate–polyacrylamide gel, and transferred onto nitrocellulose membranes, which were incubated with monoclonal mouse-anti-SERCA2a (1:1000 dilution, Affinity BioReagent), mouse-anti-PLB (1:1000 dilution, Affinity BioReagent), or rabbit-anti-pSer16-PLB (1:1000 dilution, Upstate Biotechnology), followed by incubation with a secondary anti-mouse antibody for SERCA2a and PLB, or an anti-rabbit antibody for pSer16-PLB. In order to detect pSer16-PLB, the homogenization buffer contained 10 mM of NaF and 1 mM of Na3VO4 to inhibit phosphatase, and the sample was heated to 37°C for 30 min. SERCA protein was detected as a 110 kDa band, while PLB and pSer16-PLB as 25 kDa bands. Blots were semiquantified using imaging software (Eastman Kodak) and corrected by comparison of glyceraldehyde phosphate dehydrogenase (GAPDH, 36 kDa).

Cytokine assay
For IL-6 and IL-10 assay, frozen LV tissues were cut into three parts as follows: (1) infarct zone containing only infarct tissue; (2) tissue less than 5 mm from the infarct zone representing the peri-infarct zone; and (3) tissue more than 5 mm from the infarct zone representing the remote zone. The tissue was homogenized. The supernatant was obtained by centrifugation (14000 r.p.m., 15 min, 4°C). Enzyme-linked immunosorbent assay was done using a commercially available kit (Bender Medsystems). Final results were expressed as pg/mg protein.

Statistical analysis
Data are presented as mean±SD. Data sets containing multiple groups were analysed by analysis of variance. Mean values between the two groups were compared by a least-significant difference test, after an F test for homogeneity of variances had been performed. If data failed to meet the requirements for equal variance, a Tamhane T2 test was used. P-values less than 0.05 were considered significant.


   Results
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
Serum lipid levels
After 10 weeks of rosuvastatin treatment, serum concentrations of total cholesterol, triglycerides, and low- and high-density lipoprotein cholesterol remained unchanged in normal and MI rats (Figure 1A).


Figure 1
View larger version (27K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Serum lipid levels (A) and left ventricular infarct size (B) in rats treated with or without rosuvastatin. Groups: NC, normal control (n = 8); NC+R, normal control plus rosuvastatin (n = 8); S, sham-operated (n = 8); MI, MI control (n = 8); MI+R, MI plus rosuvastatin (n = 6). Data are presented as mean±SD. No significant differences were found among the five groups.

 
Effect of rosuvastatin on heart weight and infarct size
LVAW, LVRW, and RVRW were significantly increased in MI rats. In comparison with the MI group, LVAW and LVRW were significantly decreased in MI+R group (P < 0.05), but RVRW was unchanged (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1 Body weight and heart weight in rats treated with or without rosuvastatin

 
No significant differences were found between MI and MI+R groups regarding LV infarct size as assessed by immunohistochemistry (31.58 ± 1.85 vs. 32.93 ± 0.97%) and echocardiography (23.84 ± 1.77 vs. 25.76 ± 2.09% at 2 weeks, 34.51 ± 2.74 vs. 36.26 ± 1.09% at 10 weeks, respectively) (Figure 1B).

Echocardiographic changes
Increased LVIDd and LVIDs with reduced LV FS were found at 2 weeks. Progressive increases in LV dimensions and LV dysfunction were observed from 2 to 10 weeks as reflected by a gradual increase in LVIDd and LVIDs, as well as decrease of LV FS.

From 8 weeks, rats receiving rosuvastatin treatment began to show a modest decrease in LVIDd and a significant decrease in LVIDs as well as a significant increase in FS compared with MI rats. However, there was no significant difference between the NC and NC+R groups (Table 2). LVIDd, LVIDs, and FS at 4 and 6 weeks in MI+R rats did not change significantly when compared with MI rats (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 2 Serial echocardiography in rats treated with or without rosuvastatin

 
Effects of rosuvastatin on haemodynamics
Systolic, diastolic, and mean BP, LVSP, and ±dp/dtmax were significantly decreased, whereas LVEDP remarkably increased in the MI group compared with S rats (Table 3). The MI+R group showed a significantly higher systolic BP, ±dp/dtmax, and lower LVEDP than the MI group. Rosuvastatin treatment in normal rats did not result in a significant change in any of these indices.


View this table:
[in this window]
[in a new window]

  		Table 3 In vivo haemodynamics in rats treated with or without rosuvastatin

 
SERCA2a and phospholamban protein expression and sarcoplasmic reticulum Ca2+ ATPase activity
SERCA2a protein expression was downregulated while PLB was overexpressed in MI rats (P < 0.01 or <0.05 vs. S). After treatment with rosuvastatin, SERCA2a protein expression was elevated (MI+R: 0.45 ± 3.8 vs. MI: 0.28 ± 2.8%, P < 0.05), but no change in PLB protein level was observed. Additionally, pSer16-PLB level did not change, resulting in decreased pSer16-PLB/PLB ratio in the MI group compared with S rats. Rosuvastatin elevated pSer16-PLB level (MI+R: 2.17 ± 9.7 vs. MI: 1.67 ± 6.6%, P < 0.05), which resulted in an increased pSer-PLB/PLB ratio (MI+R: 0.48 ± 1.3 vs. MI: 0.34 ± 5.6%, P < 0.05). Moreover, SERCA activity decreased significantly in the MI group (P < 0.01 vs. S), and this was attenuated by rosuvastatin (MI+R: 5.35 ± 0.33 vs. MI: 4.31 ± 0.32 µmol Pi/mg prot/h, P < 0.01), but was still lower than the basal level in control animals (P < 0.05 vs. S). No differences in the above indices were found among NC, NC+R, or S groups (Figure 2).


Figure 2
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 SERCA, PLB, and pSer16-PLB protein changes in heart tissue. (A) SERCA2a, PLB, and pSer16-PLB protein detected by immunoblot analyses. (B) SERCA2a, PLB, and pSer16-PLB protein levels, measured by western blotting. (C) SERCA activity in rats treated with or without rosuvastatin. Lane 1, normal control (n = 8); lane 2, normal control plus rosuvastatin (n = 8); lane 3, sham-operated (n = 8); lane 4, MI control (n = 8); lane 5, MI plus rosuvastatin (n = 6); Groups: NC, normal control (n = 8); NC+R, normal control plus rosuvastatin (n = 8); S, sham-operated (n = 8); MI, MI control (n = 8); MI+R, MI plus rosuvastatin (n = 6). Data are presented as mean±SD. *P < 0.05, **P < 0.01 vs. S group; +P < 0.05, ++P < 0.01 vs. MI group.

 
Interleukin-6 and interleukin-10 levels
The IL-6 and IL-10 levels in the infarct zones of MI rats were significantly lower than in the myocardium of S rats, and rosuvastatin did not affect IL-6 and IL-10 expression in this region. In the peri-infarct zone of MI rats, the IL-6 and IL-10 levels were increased, and rosuvastatin treatment significantly decreased IL-6 level (P < 0.01) and increased IL-10 level (P < 0.05). Additionally, in the remote zone, elevated IL-6 and IL-10 levels were lower than those in the peri-infarct zone. Rosuvastatin treatment significantly prevented the elevation of IL-6 (P < 0.05) and enhanced increase of IL-10 level (P < 0.01). However, no significant difference existed among NC, NC+R, or S groups (Figure 3).


Figure 3
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3 Effects of rosuvastatin on IL-6 (A) and IL-10 (B) levels in rat LV. Data are presented as mean±SD. *P < 0.05, **P < 0.01 vs. S group. Groups: NC, normal control (n = 8); NC+R, normal control plus rosuvastatin (n = 8); S, sham-operated (n = 8); MI, MI control (n = 8); MI+R, MI plus rosuvastatin (n = 6).

 

   Discussion
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
The efficacy of statin therapy in patients with established chronic cardiac dysfunction is a subject of much debate.14 In our experiments, rosuvastatin at an effective and safe dose for vascular and cardiac protection9,15 prevented LV remodelling and dysfunction in rats, as assessed by echocardiographic and haemodynamic indices. However, serial echocardiographic and histological data revealed that rosuvastatin given one day after coronary artery ligation had no effect on MI size. Furthermore, MI size was enlarged at 10 weeks compared with 2 weeks, consistent with the generally accepted view that the lack of elastic recoil contributes to the thinning and expansion of the infarct region, which frequently progresses after MI and results in cardiac enlargement and cardiac dysfunction with time.16 Because most of the haemodynamic and echocardiographic parameters were partially preserved by rosuvastatin therapy while the infarct size was not reduced, the beneficial effect of rosuvastatin in cardiac function preservation is most likely due to a direct effect of rosuvastatin on the non-infarcted myocardium rather than to a reduction in infarct size. Moreover, rosuvastatin did not lead to a significant change in serum lipid levels, possibly because the lipids are relatively low in normal rats and statins do not usually modify the lipid profile in rats.17 Thus, the beneficial effects appear to be independent of lipid-lowering. The mechanisms for prevention of LV function deterioration by rosuvastatin may be due to its pleiotropic effect such as improvement of endothelial function, inhibition of myocardial hypertrophy, reduction of cardiomyocyte loss by apoptosis, decrease of oxidative stress, and restoration of neurohormonal imbalance.18 But the more important mechanism may be related to intracellular Ca2+ regulation of the remaining surviving myocytes in the LV.

It is well known that intracellular calcium flux is an important mechanism in cardiac myocyte contractility. In this experiment, we found a significant decrease of SERCA2a protein expression and SERCA activity, and increased protein expression of PLB in MI rats, which agree with our previous findings.19 Additionally, we found that pSer16-PLB/PLB ratio decreased, although pSer16-PLB did not change in MI rats. As reported by a previous study, the amount of Ca2+ pumped by SERCA is enhanced when PLB is phosphorylated and reduced when PLB is dephosphorylated.4 Reduced SERCA2a expression and SERCA activity, in combination with the elevated inhibitory effects of dephosphorylated PLB, lead to systolic and diastolic dysfunction in rats with MI. Thus, it can be postulated that the decrease in the pSer16-PLB/PLB ratio inhibits SERCA activity and may be associated with cardiac dysfunction.

We also found that 10 weeks of treatment of MI rats with rosuvastatin was associated with a partial prevention of the decrease in SERCA2a expression and function and the pSer16-PLB/PLB ratio. This is in accordance with our previous study which showed that SERCA expression is up-regulated in cultured neonatal rat ventricular myocytes with simvastatin.8 Studies indicate that statins induce alterations in mitochondrial and SR function and affect calcium homeostasis in skeletal muscle cells, coronary smooth muscle cells, and vascular smooth muscle cells,20–22 which may be related to the changes in SERCA2a and PLB that we demonstrated in this study. Nevertheless, to the best of our knowledge, there is a marked scarcity of studies that explore the specific mechanisms by which statins influence SERCA and PLB expression.

Inflammatory mechanisms play an important role in post-infarction myocardial dysfunction. Recent experiments suggest that cytokines, such as tumour necrosis factor, and the IL-1 and IL-6 family, are expressed in the myocardium in response to injury. However, long-term expression of these molecules may be counterproductive, as they lead to cardiac decompensation. Cardiac proinflammatory cytokines act in a partly negative inotropic manner, inhibit myocyte contractility, lead to the destruction of cardiomyocytes, and result in myocardial fibrosis and apoptosis.23 On the other hand, IL-10 is one of most important anti-inflammatory cytokines. This has been confirmed in lipopolysaccharide-stimulated peripheral blood mononuclear cells from patients with chronic cardiac dysfunction.24 We found significant increases of IL-6 and IL-10 in the peri-infarct and remote LV zones of MI rats. These observations suggest that cytokines are important modulators in the post-infarction remodelling process.

According to some previous studies, cytokine activation in the heart may affect SERCA and PLB expression. Treatment with IL-6 significantly decreases SERCA gene expression and protein levels in cultured neonatal rat ventricular myocytes.25,26 IL-6 suppresses SR function, possibly through induction and activation of iNOS at an early stage.27 In view of these considerations, we sought to examine the expression of IL-6 and IL-10 in normal and failing rat hearts after rosuvastatin treatment. Our study found that after rosuvastatin therapy, the up-regulation of IL-6 level was partially prevented and IL-10 concentration was raised to an even higher level. Thus, we deduce that the elevated myocardial expression of IL-6 and IL-10 may result in SERCA and PLB changes that are responsible for impairing the ability of the heart to contract. So the restoration of cytokine balance may result in the partial recovery of calcium-regulatory protein levels induced by rosuvastatin.

However, whether the changes in cytokines and calcium-handling proteins are independent because of pleiotropic effects of rosuvastatin, or an interaction exists between these changes, remains unclear. It is also possible that inhibition of the isoprenoid biosynthesis pathway and subsequent changes in the signal transduction of myocytes evoked by rosuvastatin potentially play a critical role.28 The specific mechanism requires further investigation.

In conclusion, rosuvastatin is effective in preventing LV remodelling and myocardial dysfunction and this may be of clinical significance when applied to the treatment of patients with MI and cardiac dysfunction. The mechanisms underlying these beneficial effects may be related to normalization of Ca2+-regulatory protein content, as well as depletion of IL-6 level and elevation of IL-10 level, independent of the lipid-lowering effect.

Limitations
Protein expressions of other calcium regulatory proteins such as L-type calcium channel, ryanodine receptor, and Na+/Ca2+ exchanger in LV myocardium are also important for improvement of cardiac function. Further study will be necessary to explore whether rosuvastatin treatment can affect the expression of these proteins.


   Funding
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
This research was supported by the National Science Foundation of China (Grant no. 30470715 and 30870939), the Research Fund for the Doctoral Program of Higher Education of China (no. 20040335118), and supported in part by the E-Institute of Shanghai Municipal Education Commission of China (no. E-04010).


   Acknowledgements
 
We express our sincere gratitude to Professor Iain C. Bruce (Zhejiang University) for revising the manuscript.

Conflict of interest: none declared.


   Notes
Top
 Notes
Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
{dagger} Both authors contributed equally to this work. Back


   References
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

  1. Vangheluwe P, Raeymaekers L, Dode L, Wuytack F. Modulating sarco(endo) plasmic reticulum Ca2+ ATPase 2 (SERCA2) activity: cell biological implications. Cell Calcium (2005) 38:291–302.[CrossRef][Web of Science][Medline]
  2. Periasamy M, Huke S. SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility. J Mol Cell Cardiol (2001) 33:1053–1063.[CrossRef][Web of Science][Medline]
  3. Piacentino V III, Weber CR, Chen X, Weisser-Thomas J, Margulies KB, Bers DM, Houser SR. Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res (2003) 92:651–658.[Abstract/Free Full Text]
  4. Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res (1998) 37:279–289.[Free Full Text]
  5. Tavazzi L, Tognoni G, Franzosi MG, Latini R, Maggioni AP, Marchioli R, Nicolosi GL, Porcu M. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (2004) 6:635–641.[Abstract/Free Full Text]
  6. Kjekshus J, Dunselman P, Blideskog M, Eskilson C, Hjalmarson A, McMurray JV, Waagstein F, Wedel H, Wessman P, Wikstrand J. A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics. Eur J Heart Fail (2005) 7:1059–1069.[Abstract/Free Full Text]
  7. Ohara Y, Hiasa Y, Hosokawa S, Miyazaki S, Ogura R, Miyajima H, Yuba K, Suzuki N, Takahashi T, Kishi K, Ohtani R. Impact of hydroxymethylglutaryl coenzyme A reductase inhibition on left ventricular remodeling in patients with acute anterior myocardial infarction after primary coronary angioplasty. Int Heart J (2005) 46:987–995.[Medline]
  8. Zheng X, Hu SJ. Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin (2005) 26:696–704.[CrossRef][Web of Science][Medline]
  9. Jones SP, Gibson MF, Rimmer DM III, Gibson TM, Sharp BR, Lefer DJ. Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol (2002) 40:1172–1178.[Abstract/Free Full Text]
  10. Mozaffarian D, Minami E, Letterer RA, Lawler RL, McDonald GB, Levy WC. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. Am J Cardiol (2005) 96:1699–1704.[CrossRef][Web of Science][Medline]
  11. Goldman S, Raya TE. Rat infarct model of myocardial infarction and heart failure. J Card Fail (1995) 1:169–177.[CrossRef][Medline]
  12. Kodavanti PR, Cameron JA, Yallapragada PR, Desaiah D. Effect of chlordecone (Kepone) on calcium transport mechanisms in rat heart sarcoplasmic reticulum. Pharmacol Toxicol (1990) 67:227–234.[Web of Science][Medline]
  13. Jones LR. Mg2+ and ATP effects on K+ activation of the Ca2+-transport ATPase of cardiac sarcoplasmic reticulum. Biochim Biophys Acta (1979) 557:230–242.[Medline]
  14. van der Harst P, Voors AA, van Gilst WH, Bohm M, van Veldhuisen DJ. Statins in the treatment of chronic heart failure: a systematic review. PLoS Med (2006) 3:e333.[CrossRef][Medline]
  15. Sironi L, Gianazza E, Gelosa P, Guerrini U, Nobili E, Gianella A, Cremonesi B, Paoletti R, Tremoli E. Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects. Arterioscler Thromb Vasc Biol (2005) 25:598–603.[Abstract/Free Full Text]
  16. Nicolosi GL. Cardiac remodeling and failure after myocardial infarction. J Cardiovasc Risk (1994) 1:310–313.[Medline]
  17. Endo A, Tsujita Y, Kuroda M, Tanzawa K. Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochim Biophys Acta (1979) 575:266–276.[Medline]
  18. Tousoulis D, Charakida M, Stefanadi E, Siasos G, Latsios G, Stefanadis C. Statins in heart failure. Beyond the lipid lowering effect. Int J Cardiol (2007) 115:144–150.[CrossRef][Web of Science][Medline]
  19. Sun YL, Hu SJ, Wang LH, Hu Y, Zhou JY. Effect of beta-blockers on cardiac function and calcium handling protein in postinfarction heart failure rats. Chest (2005) 128:1812–1821.[Abstract/Free Full Text]
  20. Perez-Guerrero C, Alvarez de Sotomayor M, Herrera MD, Marhuenda E. Endothelium modulates contractile response to simvastatin in rat aorta. Z Naturforsch [C] (2000) 55:121–124.
  21. Sirvent P, Mercier J, Vassort G, Lacampagne A. Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle. Biochem Biophys Res Commun (2005) 329:1067–1075.[CrossRef][Web of Science][Medline]
  22. Hill BJ, Dixon JL, Sturek M. Effect of atorvastatin on intracellular calcium uptake in coronary smooth muscle cells from diabetic pigs fed an atherogenic diet. Atherosclerosis (2001) 159:117–124.[CrossRef][Web of Science][Medline]
  23. Candia AM, Villacorta Junior H, Mesquita ET. Immune-inflammatory activation in heart failure. Arq Bras Cardiol (2007) 89:201–208.
  24. Bolger AP, Sharma R, von Haehling S, Doehner W, Oliver B, Rauchhaus M, Coats AJ, Adcock IM, Anker SD. Effect of interleukin-10 on the production of tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with chronic heart failure. Am J Cardiol (2002) 90:384–389.[CrossRef][Web of Science][Medline]
  25. Tanaka T, Kanda T, Takahashi T, Saegusa S, Moriya J, Kurabayashi M. Interleukin-6-induced reciprocal expression of SERCA and natriuretic peptides mRNA in cultured rat ventricular myocytes. J Int Med Res (2004) 32:57–61.[Web of Science][Medline]
  26. Villegas S, Villarreal FJ, Dillmann WH. Leukemia Inhibitory Factor and Interleukin-6 downregulate sarcoplasmic reticulum Ca2+ ATPase (SERCA2) in cardiac myocytes. Basic Res Cardiol (2000) 95:47–54.[CrossRef][Web of Science][Medline]
  27. Yu XW, Chen Q, Kennedy RH, Liu SJ. Inhibition of sarcoplasmic reticular function by chronic interleukin-6 exposure via iNOS in adult ventricular myocytes. J Physiol (2005) 566:327–340.[Abstract/Free Full Text]
  28. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol (2001) 21:1712–1719.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Yang, Y.
Right arrow Articles by Fu, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, Y.
Right arrow Articles by Fu, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?