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Frontiers of Medicine

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ISSN 2095-0225(Online)

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Front. Med.    2015, Vol. 9 Issue (4) : 444-456    https://doi.org/10.1007/s11684-015-0421-z
RESEARCH ARTICLE
Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling
Samuel Chege Gitau1,3,Xuelian Li1,Dandan Zhao1,Zhenfeng Guo1,Haihai Liang1,Ming Qian1,Lifang Lv1,Tianshi Li1,Bozhi Xu1,Zhiguo Wang2,Yong Zhang1,Chaoqian Xu1,Yanjie Lu1,2,Zhiming Du4,Hongli Shan1,*(),Baofeng Yang1,2,*()
1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150081, China
2. Institute of Cardiovascular Research, Harbin Medical University, Harbin 150081, China
3. Department of Pharmacy and Complementary Medicine, School of Health Sciences, Kenyatta University, P.O. BOX 43844-00100, Nairobi, Kenya
4. Institute of Clinical Pharmacy, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China
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Abstract

Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg−1·d−1); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L−1) was treated with the human equivalent of low (10 or 100 µmol·L−1) and high (1000 µmol·L−1) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.
Keywords aspirin      Akt      cardiac hypertrophy      GSK-3β      Wnt/β-catenin     
Corresponding Author(s): Hongli Shan,Baofeng Yang   
Just Accepted Date: 28 October 2015   Online First Date: 17 November 2015    Issue Date: 26 November 2015
 Cite this article:   
Samuel Chege Gitau,Xuelian Li,Dandan Zhao, et al. Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling[J]. Front. Med., 2015, 9(4): 444-456.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0421-z
https://academic.hep.com.cn/fmd/EN/Y2015/V9/I4/444
Fig.1  Effect of aspirin on cardiac morphology and function. (A) Representative echocardiographic images of ventricular myocardium, including the B-mode (upper panel) and M-mode (lower panel) recordings. The number (n) of mice analyzed per group is given in Table 1. Aspirin (10 mg·kg−1·d−1) restored the TAC-induced decrease in chamber size and the increase in wall thickness. (B) Box and whisker plots summarizing the changes in the ejection fraction (% EF) and fractional shortening (% FS). Aspirin normalized cardiac function. The data were presented as mean±SEM; n = 6; #P<0.05 vs. TAC; * P<0.05 vs. Control. (C) Representative electron micrographs for the ultrastructural analysis of the ventricular myocardium. No tissue swelling occurred in the control group. By contrast, the non-treated TAC group displayed marked degenerative changes as indicated by swollen mitochondria with amorphous matrix densities, distended myofibrils, and irregular Z lines. However, the aspirin-treated group had fewer and smaller alterations; n = 3; magnification, 15 000×; HV, 80 kV; scale bar calibration, 2 µm. (D) Bar graph summarizing the heart weight (HW) normalized to body weight (BW) or tibia length (TL). The data were presented as mean±SEM; n is given in the text; ## P<0.0001 vs. TAC; * P<0.05 vs. Control. (E) Bar graph summarizing the measured left ventricular mass based on the M-mode echocardiography. The data were presented as mean±SEM; n = 6; # P<0.05 vs. TAC; * P<0.05 vs. Control. Control, sham-operated mice treated with vehicle (PBS+ 0.65% ethanol); TAC, TAC-operated mice treated with vehicle; Aspirin+ TAC, TAC-operated mice treated with 10 mg·kg−1·d−1 aspirin (human equivalent dose of 1 mg·kg−1·d−1).
Control (n = 6) TAC (n = 13) Aspirin+ TAC (n = 7)
mean SEM mean SEM *P mean SEM # P
LVAW; d mm 0.74 0.16 1.01 0.24 0.020 0.76 0.25 0.034
LVAW; s mm 1.07 0.27 1.39 0.31 0.045 1.08 0.29 0.042
LVID; d mm 3.74 0.47 3.23 0.46 0.035 3.69 0.43 0.040
LVID; s mm 2.71 0.55 2.02 0.46 0.010 2.69 0.59 0.010
LVPW; d mm 0.69 0.10 1.14 0.48 0.049 0.59 0.13 0.048
LVPW; s mm 0.98 0.17 1.37 0.38 0.029 0.91 0.24 0.009
LV Vol; d µl 60.95 16.72 43.12 13.79 0.023 58.61 15.26 0.030
LV Vol; s µl 28.84 13.27 14.24 7.27 0.005 28.58 13.91 0.005
Tab.1  Effects of aspirin (10 mg·kg−1·d−1) on cardiac function, as measured by echocardiography
Fig.2  Effects of aspirin on biomarkers of cardiac hypertrophy in the ventricular myocardium. (A) Real-time PCR analysis of ANP, BNP, andβ-MHC mRNA. (B) A western blot analysis of β-MHC protein (upper panel) and statistical analysis (lower panel). Aspirin (10 mg·kg−1·d−1) normalized the abnormal upregulation of the hypertrophic biomarker in vivo. The data were presented as mean±SEM; n = 3; #P<0.05 vs. TAC; *P<0.05 vs. Control. Control, sham-operated mice treated with vehicle (PBS+ 0.65% ethanol); TAC, TAC-operated mice treated with vehicle; aspirin+ TAC, TAC-operated mice treated with 10 mg·kg−1·d−1 aspirin (human equivalent dose of 1 mg·kg−1·d−1).
Fig.3  Effects of aspirin on biomarkers of VH in vitro. (A) Real-time PCR analysis of ANP, and BNP, and β-MHC mRNA levels in ANG II (10 nmol·L−1) induced the NRVM hypertrophy model. One-way ANOVA showed that aspirin normalized the abnormal upregulation of hypertrophic biomarkers in a dose-dependent manner. The data were presented as mean±SEM; n = 4 for each individual experiment; #P<0.05 vs. ANG II (10 nmol·L−1); *P<0.05 vs. Control. (B) Representative western blot analysis of β-MHC protein expression (upper panel) and the corresponding statistical analysis (lower panel). The data were presented as mean±SEM; n = 4 for each individual experiment; #P<0.05 vs. ANG II (10 nmol·L−1); *P<0.05 vs. Control. (C) Representative immunohistochemical staining of NRVM photographed by fluorescence microscopy (upper panel) and its statistical analysis (bottom panel). DAPI and α-actinin were used to stain the nuclei and cytoplasm, respectively. Aspirin (100 µmol·L−1)-treated NRVM showed reduced cell size compared to non-treated cells; 10 cells were scored per field. The data were presented as mean±SEM; neonatal rats per individual experiment, n = 3; #P<0.05 vs. ANG II (10 nmol·L−1); *P<0.05 vs. Control. NRVM, primary neonatal cardiomyocytes; Control, NRVM treated with vehicle (DMSO at a final concentration of<0.01%); ANG II (10 nmol·L−1), NRVM treated with ANG II alone; Aspirin+ ANG II, NRVM treated with aspirin (varying concentrations) + ANG II.
Fig.4  Effects of aspirin on Wnt/β-catenin expression. (A) Real-time PCR analysis of β-catenin mRNA expression in cardiac tissue (left) and NVRMs (right). One-way ANOVA showed aspirin treatment (10 mg·kg−1·d−1) significantly reduced β-catenin expression in a dose dependent manner. The data were presented as mean±SEM; n = 3; #P<0.05 vs. TAC or ANG II 10 nmol·L−1; *P<0.05 vs. Control. (B) Representative western blot analysis of total β-catenin protein expression (upper panel) in cardiac tissue (left) and NRVMs (right), with the corresponding statistical analysis (lower panel). Treatment significantly reduced β-catenin protein expression; n = 3; #P<0.05 vs. TAC or ANG II 10 nmol·L−1; *P<0.05 vs. Control. (C) Representative western blot analysis of cytosolic and nuclear β-catenin protein expression in cardiac tissue (left) and the mean data of band density (right). The cytoplasmic and nuclear β-catenin fractions were normalized to GAPD and lamin B1, respectively. Aspirin significantly reduced the nuclear β-catenin expression in aspirin-treated and TAC-operated mice. The data were presented as mean±SEM; n = 3; #P<0.05 vs. TAC; *P<0.05 vs. Control. Control, sham-operated mice treated with vehicle (PBS+ 0.65% ethanol); TAC, TAC-operated mice treated with PBS+ 0.65% ethanol; Aspirin+ TAC, TAC-operated mice treated with aspirin 10 mg·kg−1·d−1 (human equivalent dose of 1 mg·kg−1·d−1).
Fig.5  Effects of aspirin and Dickkopf-1 on β-catenin and hypertrophy markers expression. (A) Real-time PCR analysis of β-catenin, ANP, BNP, and β-MHC mRNA. (B) Representative western blot analysis of total β-catenin protein expression in NRVM (upper panel) and mean data of band density (lower panel). NVRMs were incubated with or without aspirin (100 µmol·L−1) or with DKK-1 (200 nmol·L−1), a specific Wnt-β-catenin signaling inhibitor, in the presence or absence of ANG II (10 nmol·L−1). The anti-hypertrophic effects of aspirin and DKK were similar. The data were presented as mean±SEM, neonatal rats per individual experiment, n = 3, *P<0.05 vs. Control, #P<0.05 vs. Control. Control, NVRM treated with DMSO to a final concentration of<0.01%; ANG II (10 nmol·L−1), NRVM treated with ANG II alone; Aspirin+ ANG II, NRVM treated with aspirin (100 or 1000 µmol·L−1 concentrations) + ANG II; DKK+ ANG II, NVRM treated with Dickkopf (200 nmol·L−1) and ANG II.
Fig.6  Effects of aspirin on Akt and GSK-3β expression. (A) Representative western blot analysis of p-Akt (Ser473) protein expression in cardiac tissue (upper panel) and the mean data of band density (lower panel). Aspirin abrogated the abnormal upregulation of p-Akt (Ser473) protein expression. The data were presented as mean±SEM, n = 4; #P<0.05 vs. TAC, *P<0.05 vs. Control. (B) Representative western blot analysis of p-Akt (Ser473) protein expression in NVRM treated with aspirin (100 or 1000 µmol·L−1) or DKK-1 (200 nmol·L−1) in the presence or absence of ANG II (10 nmol·L−1; upper panel). The mean data of band density (lower panel) were presented as mean±SEM, n = 3; #P<0.05 vs. ANG II, *P<0.05 vs. Control. (C) Representative western blot analysis of the phosphorylated and inactive forms of GSK-3β (Ser9) protein levels in cardiac tissue (upper panel) and the mean data of band density (lower panel). Aspirin abrogated the abnormal upregulation of GSK-3β (Ser9) protein expression. The data were presented as mean±SEM, n = 4; #P<0.05 vs. TAC, * P<0.05 vs. Control. (D) Representative western blot analysis of p-GSK-3β (Ser9) protein expression in NVRM treated with aspirin (100 or 1000 µmol·L−1) or DKK-1 (200 nmol·L−1) in the presence or absence of ANG II (10 nmol·L−1; upper panel) and the mean data of band density (lower panel). The data were represented as mean±SEM, n = 3; # P<0.05 vs. ANG II (10 nmol·L−1), *P<0.05 vs. Control. NVRM, primary cultured neonatal cardiomyocytes; Control, sham-operated mice treated with vehicle (PBS+ 0.65% ethanol) or NVRM treated with DMSO to a final concentration of<0.01%; TAC, TAC-operated mice treated with PBS+ 0.65% ethanol; Aspirin+ TAC, TAC-operated mice treated with aspirin 10 mg·kg−1·d−1 (human equivalent dose of 1 mg·kg−1·d−1); ANG II (10 nmol·L−1), NRVM treated with ANG II alone; Aspirin+ ANG II, NRVM treated with aspirin (varying concentrations) + ANG II; DKK-1+ ANG II, NVRM treated with Dickkopf 1(200 nmol·L−1) and ANG II.
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