Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway

Zhang, Qian; Wang, Hong; Yang, Yue-Jin; Dong, Qiu‐Ting; Wang, Tianjie; Qian, Hai-Yan; Li, Na; Wang, Ximei; Jin, Chen

doi:10.1016/j.ijcard.2014.07.071

Cited by 34 publications

(27 citation statements)

References 45 publications

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“…In addition, atorvastatin significantly improves the degree of ventricular remodeling and heart function. Our results suggested that atorvastatin may improve HF by decreasing the plasma NT-proBNP, IL-6, IL-10, and hs-CRP levels; this observation was consistent with those of previous studies, which revealed a significant correlation between atorvastatin and NT-proBNP, IL-6, IL-10, and hs-CRP (Bennaceur et al, 2014;Zhang et al, 2014). In addition, a previous study has shown that the atorvastatin-induced improvement in heart function (in HF patients) is unaffected by the blood lipid level and improvements in the degree of coronary lesion degree , which analyzed the role of atorvastatin in reducing low-density lipoprotein cholesterol levels and increasing high-density lipoprotein (HDL) levels (Xu et al, 2014).…”

Section: Discussionsupporting

confidence: 93%

Effect of atorvastatin on plasma NT-proBNP and inflammatory cytokine expression in patients with heart failure

et al. 2015

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ABSTRACT. The aim of this study was to explore the effect of atorvastatin intervention on plasma N-terminal pro-B-type natriuretic peptide (NTproBNP) and inflammatory cytokine levels in patients with heart failure (HF). One hundred and twenty-three HF patients were selected from our hospital and randomly divided into control (N = 61) and observation (N = 62) groups; the former received conventional treatment, while the latter were given conventional treatment combined with atorvastatin. Plasma NT-proBNP, inflammatory cytokines [high-sensitive C-reactive protein (hs-CRP), interleukin (IL)-6, IL-10] and cardiac function [left ventricular enddiastolic dimension (LVEDD), left ventricular ejection fraction (LVEF), enddiastolic maximum flow rate ratio (E/A)] were compared among groups. The effective rate of treating HF significantly increased after atorvastatin treatment. The plasma NT-proBNP, IL-6, IL-10, hs-CRP, and LVEDD levels significantly decreased (P < 0.05), while the LVEF and E/A levels significantly increased (P < 0.05) in the observation group compared to the control group and before intervention. The NT-proBNP and cytokine levels significantly differed among patients with different classes of heart function (P < 0.05); the NT-proBNP and cytokine levels increased with the severity of heart function. Pearson's correlation analysis revealed a negative correlation between the NT-proBNP and inflammatory cytokine levels and LVEF and E/A values, and a positive correlation between these factors and LVEDD (P < 0.05). In conclusion, atorvastatin significantly improves cardiac function; the mechanism atorvastatin action was related to the decrease in plasma NT-proBNP and inflammatory cytokine levels.

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Section: Discussionsupporting

confidence: 93%

Effect of atorvastatin on plasma NT-proBNP and inflammatory cytokine expression in patients with heart failure

et al. 2015

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“…The surprising increases in both ATV ‐MSCs recruitment and survival in current study, which are the fundamental and bottle‐neck for therapeutic efficacy in cell therapy, were mainly ascribed to the prominent effects of SDF‐1‐driven targeted homing and strong antiapoptotic properties of ATV ‐MSCs by the combination protocol. Another contributing factor for ATV ‐MSCs survival was the powerful ameliorating of intense inflammatory harsh microenvironment in the infarcted region by intensive ATV treatment with strong anti‐inflammatory and antiapoptotic effects, as in the current study, our previous studies , and the studies of others . To the best of our knowledge, this is the first report to find the remarkable enhancement of SDF‐1 expression in infarcted myocardium by intensive ATV treatment over the entire 4‐week period of AMI, and the mid‐term stage (the 2nd week) of AMI was the optimal time window period of ATV ‐MSCs transplantation with the clinically feasible combination protocol in preclinical AMI model.…”

Section: Discussionsupporting

confidence: 75%

Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction

Xiong

et al. 2019

Stem Cells Translational Medicine

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Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV‐pretreated mesenchymal stem cells (MSCs) (ATV‐MSCs) at 1 week post‐acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV‐MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell‐derived factor‐1 (SDF‐1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV‐MSCs at early (Early1, Early2, Early3), mid‐term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF‐1 expression 1.5∼2.6‐fold in peri‐infarcted region with inhibited inflammation. ATV‐MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%∼24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%∼16.2%, and reduced infarct size in all groups 6 weeks post‐AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV‐MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV‐MSCs were much more effective than single administration during early and mid‐term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV‐MSCs combined with intensive ATV administration at mid‐term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019;8:1068–1083

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“…Myocardial apoptosis mediated by oxidative stress and inflammatory response, and decrease of viable myocardial cells are the major causes of heart failure in AMI patients. Mitochondrial dysfunction of ischemic myocardial cells leads to massive synthesis and secretion of reactive oxygen species (ROS), induces oxidative stress response in cells, alters mitochondrial membrane permeability and causes myocardial apoptosis (21)(22)(23). Inhibiting the expression of inflammatory factors in myocardial tissues can effectively alleviate AMI-induced cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Fluvastatin protects myocardial cells in mice with acute myocardial infarction through inhibiting RhoA/ROCK pathway

Wang

et al. 2020

Exp Ther Med

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Protective effect of fluvastatin (Flu) on myocardial cells in mice with acute myocardial infarction (AMI) and the mechanism were explored. Forty C57B/L6 mice in similar physiological status were selected and randomly divided into sham operation (Sham) group (n=10), AMI group (n=10), Flu group (n=10) and Flu + Angiotensin II (Ang II) (Ang II) group (n=10). The pathological changes in heart tissues were detected via hematoxylin and eosin (H&E) staining, and apoptosis of myocardial cells was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined using relevant kits, and the expression levels of Ras homolog gene family (Rho)-associated coiled-coil protein kinase 1 (ROCK1), ROCK2, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax) and nuclear factor-κB (NF-κB) in the infarction region were determined using Western blotting. The infarction area in mice in Flu group was significantly smaller than that in AMI group. In AMI group, the level of MDA in the serum and infarction tissues was remarkably higher than that in Sham group (P<0.05), while that of SOD significantly declined (P<0.05). The level of MDA in Flu group was obviously lower than that in AMI group (P<0.05). The expression levels of Bax, NF-κB, ROCK1 and ROCK2 were obviously higher in AMI group than those in Sham group, while they were obviously lower in Flu group than those in AMI group (P<0.05). After the Rho member A (RhoA)/ROCK pathway agonist Ang II was added, the mitigation effect of Flu on myocardial apoptosis in the infarction region in AMI mice was evidently weakened. Flu mitigates AMI-induced myocardial apoptosis in mice, and the possible mechanism is that the inflammatory and oxidative stress responses activated and mediated by RhoA/ROCK are effectively inhibited.

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Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway

Cited by 34 publications

References 45 publications

Effect of atorvastatin on plasma NT-proBNP and inflammatory cytokine expression in patients with heart failure

Effect of atorvastatin on plasma NT-proBNP and inflammatory cytokine expression in patients with heart failure

Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction

Fluvastatin protects myocardial cells in mice with acute myocardial infarction through inhibiting RhoA/ROCK pathway

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